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Persistent elevation of high mobility group box-1 protein (HMGB1) in patients with severe sepsis and septic shock
Abstract
To study the systemic release and kinetics of high mobility group box-1 protein (HMGB1) in relation to clinical features in a population of patients with severe sepsis or septic shock and to compare these with the kinetics of the cytokines interleukin-6, interleukin-8, interleukin-10, and tumor necrosis factor-alpha.
Prospective study of two cohorts of patients.
Intensive care unit and infectious disease clinic at Karolinska University Hospital Huddinge.
Twenty-six patients with severe sepsis, 33 patients with septic shock, and a reference group of five patients with sepsis.
None.
Sixty-four patients were included, ten of whom died within 28 days. Cytokine levels were measured at five time points during the first week after admission and were correlated to Acute Physiology and Chronic Health Evaluation II and Sepsis-related Organ Failure Assessment scores. Two HMGB1 assays were used. Both demonstrated delayed kinetics for HMGB1 with high levels on inclusion that remained high throughout the study period. Serum concentration at 144 hrs, the last sampling point, was 300 times higher, 34,000 +/- 76,000 pg/mL (mean +/- sd), than any of the other cytokines. This study, however, found no predictable correlation between serum levels of HMGB1 and severity of infection. We did quite unexpectedly find significantly lower levels of HMGB1 in nonsurvivors compared with survivors as measured by our main assay, but the other showed no difference between the two groups. Levels of interleukin-6, interleukin-8, interleukin-10, and tumor necrosis factor-alpha correlated significantly with severity of disease, and all were significantly higher in patients with septic shock compared with those with severe sepsis. Neither of these comparisons showed significant correlations for HMGB1.
This is the first prospective study assessing the release over time of HMGB1 in a population of patients with sepsis, severe sepsis, or septic shock. Levels remained high in the majority of patients up to 1 wk after admittance, indicating that the cytokine indeed is a downstream and late mediator of inflammation. Further studies are required to fully define the relationship of HMGB1 to severity of disease.
... HMGB1 is also involved in cognitive impairment-related diseases, such as Alzheimer's disease (AD) and traumatic brain injury (TBI) [11,12]. Notably, HMGB1 is a late mediator of inflammation in sepsis [13]. In an animal model of SAE, the serum levels of HMGB1 are increased in sepsis survivors, which remains elevated for at least 4 weeks after CLP [14,15]. ...
... Raw data were recorded in NOR on day 14 after surgery. In our study, the bands were classified as delta oscillations (1-4 Hz), theta oscillations (4-8 Hz), alpha oscillations (8-12 Hz), beta oscillations (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), and gamma oscillations . The signals were filtered with a passband of 0.3-300 Hz and further amplified and digitized at 2 kHz. ...
... In addition, a previous study reported that double-stranded RNA dependent protein kinase could physically interact with inflammasome components and mediates inflammasome activation, thus regulating release of HMGB1 [31]. Interestingly, HMGB1 is also a late mediator of inflammation in sepsis [13] and participates in the amplification of neuroinflammation [32]. However, there are few studies on the role of HMGB1 in SAE. ...
... HMGB1 is also involved in cognitive impairment-related diseases, such as Alzheimer's disease (AD) and traumatic brain injury (TBI) [11,12]. Notably, HMGB1 is a late mediator of inflammation in sepsis [13]. In an animal model of SAE, the serum levels of HMGB1 are increased in sepsis survivors, which remains elevated for at least 4 weeks after CLP [14,15]. ...
... Raw data were recorded in NOR on day 14 after surgery. In our study, the bands were classified as delta oscillations (1-4 Hz), theta oscillations (4-8 Hz), alpha oscillations (8-12 Hz), beta oscillations (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), and gamma oscillations . The signals were filtered with a passband of 0.3-300 Hz and further amplified and digitized at 2 kHz. ...
... In addition, a previous study reported that double-stranded RNA dependent protein kinase could physically interact with inflammasome components and mediates inflammasome activation, thus regulating release of HMGB1 [31]. Interestingly, HMGB1 is also a late mediator of inflammation in sepsis [13] and participates in the amplification of neuroinflammation [32]. However, there are few studies on the role of HMGB1 in SAE. ...
Background
Microglial activation-mediated neuroinflammation is one of the essential pathogenic mechanisms of sepsis-associated encephalopathy (SAE). Mounting evidence suggests that high mobility group box-1 protein (HMGB1) plays a pivotal role in neuroinflammation and SAE, yet the mechanism by which HMGB1 induces cognitive impairment in SAE remains unclear. Therefore, this study aimed to investigate the mechanism of HMGB1 underlying cognitive impairment in SAE.
Methods
An SAE model was established by cecal ligation and puncture (CLP); animals in the sham group underwent cecum exposure alone without ligation and perforation. Mice in the inflachromene (ICM) group were continuously injected with ICM intraperitoneally at a daily dose of 10 mg/kg for 9 days starting 1 h before the CLP operation. The open field, novel object recognition, and Y maze tests were performed on days 14–18 after surgery to assess locomotor activity and cognitive function. HMGB1 secretion, the state of microglia, and neuronal activity were measured by immunofluorescence. Golgi staining was performed to detect changes in neuronal morphology and dendritic spine density. In vitro electrophysiology was performed to detect changes in long-term potentiation (LTP) in the CA1 of the hippocampus. In vivo electrophysiology was performed to detect the changes in neural oscillation of the hippocampus.
Results
CLP-induced cognitive impairment was accompanied by increased HMGB1 secretion and microglial activation. The phagocytic capacity of microglia was enhanced, resulting in aberrant pruning of excitatory synapses in the hippocampus. The loss of excitatory synapses reduced neuronal activity, impaired LTP, and decreased theta oscillation in the hippocampus. Inhibiting HMGB1 secretion by ICM treatment reversed these changes.
Conclusions
HMGB1 induces microglial activation, aberrant synaptic pruning, and neuron dysfunction in an animal model of SAE, leading to cognitive impairment. These results suggest that HMGB1 might be a target for SAE treatment.
... In a clinical study that involved 64 patients with septic shock and severe sepsis, Sudén-Cullberg et al. studied the kinetics of the HMGB1 molecule during the disease course. This molecule was elevated in 34 patients with severe sepsis and septic shock, and the serum concentration at 144 h, the last sampling point, was 300 times higher than any of the other cytokines evaluated during the study [37]. In another clinical study, a similar increase in plasma HMGB1 levels was observed; however, this demonstrated an association between the elevation of this molecule and sepsis severity and mortality [38]. ...
... In other murine models and clinical cases of sepsis, the serum upregulation of IL-6, TNFα, and HMGB1 was observed [31,37,39,94]. The release of these elements causes neuroinflammation. ...
Central nervous system (CNS) infections including meningitis and encephalitis, resulting from the blood-borne spread of specific microorganisms, provoke nervous tissue damage due to the inflammatory process. Moreover, different pathologies such as sepsis can generate systemic inflammation. Bacterial lipopolysaccharide (LPS) induces the release of inflammatory mediators and damage molecules, which are then released into the bloodstream and can interact with structures such as the CNS, thus modifying the blood-brain barrier's (BBB s) and blood-cerebrospinal fluid barrier s (BCSFB s) function and inducing aseptic neuroinflammation. During neuroinflammation, the participation of glial cells (astrocytes, microglia, and oligodendrocytes) plays an important role. They release cytokines, chemokines, reactive oxygen species, nitrogen species, peptides, and even excitatory amino acids that lead to neuronal damage. The neurons undergo morphological and functional changes that could initiate functional alterations to neurodegenerative processes. The present work aims to explain these processes and the pathophysiological interactions involved in CNS damage in the absence of microbes or inflammatory cells.
... When released from cells it functions as an alarmin or DAMP (Deng et al., 2019). Circulating HMGB1 is increased during endotoxemia/sepsis and antibody-mediated disruption of HMGB1-LPS binding confers resistance to sepsis (Yang et al., 2004;Sundén-Cullberg et al., 2005;Youn et al., 2008). The human and murine non-canonical inflammasome has been identified as a major contributor to sepsis (Kajiwara et al., 2014;Deng et al., 2018). ...
... HMGB1-mediated permeabilization of lysosomal membranes facilitates LPS release into the cytosol where it activates caspase-11 (Youn et al., 2011;Deng et al., 2018). Systemic HMGB1 is elevated in human septic shock patients and correlates with a worse prognosis (Hatada et al., 2005;Sundén-Cullberg et al., 2005). Therefore, it is likely that similar mechanisms are involved in cytosolic LPS delivery and caspase-4 and -5 activation in human sepsis. ...
Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disease of the gastrointestinal tract, associated with high levels of inflammatory cytokine production. Human caspases-4 and -5, and their murine ortholog caspase-11, are essential components of the innate immune pathway, capable of sensing and responding to intracellular lipopolysaccharide (LPS), a component of Gram-negative bacteria. Following their activation by LPS, these caspases initiate potent inflammation by causing pyroptosis, a lytic form of cell death. While this pathway is essential for host defence against bacterial infection, it is also negatively associated with inflammatory pathologies. Caspases-4/-5/-11 display increased intestinal expression during IBD and have been implicated in chronic IBD inflammation. This review discusses the current literature in this area, identifying links between inflammatory caspase activity and IBD in both human and murine models. Differences in the expression and functions of caspases-4, -5 and -11 are discussed, in addition to mechanisms of their activation, function and regulation, and how these mechanisms may contribute to the pathogenesis of IBD.
... From the clinical results, we propose that serum HMGB1 + EVs in sepsis patients can be used as a marker for sepsis diagnosis. Previous research has shown that HMGB1 appears to be an early stage mediator in trauma [22], while HMGB1 is conversely a latestage mediator in sepsis [23]. Wang showed that treatment of FeTPPS (a small molecule selectively inhibits HMGB1-mediated caspase-11 activation) attenuates HMGB1-and caspase-11mediated immune responses, organ damage, and lethality in endotoxemia and bacterial sepsis [24]. ...
... Numerous animal studies have revealed that HMGB1 is a negative outcome predictor of sepsis [26]. In humans, HMGB1 circulatory levels persistently increase in severe sepsis and septic shock [23,26]. This increase seems to be associated with a poor patient outcome or organ failure. ...
Extracellular vesicles (EVs) have emerged as important vectors of intercellular dialogue. High mobility group box protein 1 (HMGB1) is a typical damage-associated molecular pattern (DAMP) molecule, which is cytotoxic and leads to cell death and tissue injury. Whether EVs are involved in the release of HMGB1 in lipopolysaccharide (LPS)-induced acute liver injuries need more investigation. EVs were identified by transmission electron microscopy, nanoparticle tracking analysis (NTA), and western blotting. The co-localization of HMGB1, RAGE (receptor for advanced glycation end-products), EEA1, Rab5, Rab7, Lamp1 and transferrin were detected by confocal microscopy. The interaction of HMGB1 and RAGE were investigated by co-immunoprecipitation. EVs were labeled with the PKH67 and used for uptake experiments. The pyroptotic cell death was determined by FLICA 660-YVAD-FMK. The expression of NLRP3 (NOD-like receptor family pyrin domain containing 3) inflammasomes were analyzed by western-blot or immunohistochemistry. Serum HMGB1, ALT (alanine aminotransferase), AST (aspartate aminotransferase), LDH (lactate dehydrogenase) and MPO (myeloperoxidase) were measured using a commercial kit. The extracellular vesicle HMGB1 was detected in the serums of sepsis patients. Macrophages were found to contribute to HMGB1 release through the EVs. HMGB1-RAGE interactions participated in the loading of HMGB1 into the EVs. These EVs shuttled HMGB1 to target cells by transferrin-mediated endocytosis leading to hepatocyte pyroptosis by the activation of NLRP3 inflammasomes. Moreover, a positive correlation was verified between the sepsis serum EVs-HMGB1 level and clinical liver damage. This finding provides insights for the development of novel diagnostic and therapeutic strategies for acute liver injuries.
... HMGB1 is an evolutionarily highly conserved protein that can be released by activated macrophages, mediating inflammatory responses [27][28][29]. Clinical studies have shown a significant elevation in circulating HMGB1 levels in septic patients, positively correlating with the severity of sepsis and mortality [30,31]. Therefore, inhibiting the PARP1/HMGB1 signaling pathway in macrophages improves organ dysfunction caused by sepsis [26]. ...
Background
Sepsis-associated acute lung injury (ALI) and acute kidney injury (AKI) are common complications that significantly impact patient prognosis. Danlou tablet (DLT) is a traditional herbal preparation with anti-inflammatory and antioxidant properties. However, its therapeutic potential in sepsis remains unknown.
Methods
The impact of DLT on ALI and AKI was evaluated using the cecal ligation and puncture (CLP) experimental sepsis animal model. The effects of DLT on macrophages were observed through LPS-stimulated RAW264.7 cell line. Inflammatory cytokines, oxidative stress indicators, HE, PAS, and DHE staining, lung wet-to-dry weight ratio, and serum creatinine and urea nitrogen levels were used to assess tissue injury. Network pharmacology, molecular docking, and molecular dynamics simulations were used to explore the potential regulatory mechanisms of DLT in sepsis. Western blot and immunohistochemical staining were used to validate the expression of mechanism-related proteins.
Results
DLT inhibited the inflammatory response and oxidative stress, improved structural and functional abnormalities in lung and kidney tissues in CLP mice, and alleviated pro-inflammatory responses of LPS-stimulated macrophages. PARP1 and HMGB1 were identified as key regulatory targets. The results of in vitro and in vivo experiments suggest that DLT can effectively inhibit PARP1/HMGB1 and improve sepsis-associated ALI and AKI.
Conclusion
The present study demonstrated that DLT suppressed pro-inflammatory responses of macrophage and alleviated ALI and AKI in the CLP mice by inhibiting the transition activation of PARP1/HMGB1. These findings partially elucidate the mechanism of DLT in sepsis-associated ALI and AKI and further clarify the active components of DLT, thereby providing a scientific theoretical basis for treating sepsis with DLT.
... In a study of septic patients, significant expression of serum HMGB1 was detected 24 hours after the onset of sepsis and persisted until 96 hours, suggesting that HMGB1 is not released until sepsis is well established 24 hours later and sustains the pathological progression of sepsis [32] . An earlier prospective study of septic patients has validated that HMGB1 is a late and downstream inflammatory mediator in sepsis [33] . However, in a previous multicenter trial, no correlation was observed between plasma HMGB1 levels and disease severity, including APACHE II and SOFA scores [34] . ...
In the face of the elevated incidence and mortality rate of septic shock in the ICU, this retrospective study seeks to investigate the indicative and predictive value of high-mobility group box 1 (HMGB1) and miR-146b in patients with septic shock. Quantitative RT-PCR was employed in this study to quantify the HMGB1 and miR-146b levels in plasma samples obtained from the patient group and healthy controls. The investigation involved the comparison between the two groups and tracking changes in the patient group over time. The finding revealed that upon admission, the patient group exhibited markedly elevated relative expression levels of HMGB1, which subsequently decreased over time. Conversely, the patient group displayed significantly reduced relative expression levels of miR-146b upon admission, which subsequently increased over time compared to the control group. Receiver operating characteristic (ROC) curves showed good predictive value for HMGB1 and miR-146b. The experimental results suggest that HMGB1 and miR-146b serve as valuable and convenient biomarkers for evaluating the severity of septic shock and predicting mortality. Additionally, it is proposed that serum miR-146b may be inducible and potentially exerts a negative regulatory effect on the expression of HMGB1.
... Serum lactate has been recognized as a biomarker of sepsis prognosis, and elevated serum lactate levels are positively correlated with sepsis mortality [64]. Clinical studies have shown that circulating high mobility group box-1 (HMGB1) levels are significantly elevated and positively correlate with the severity of sepsis and mortality [65,66]. Lactate can strongly inhibit the gene expression of SIRT1 [67]. ...
Sepsis is defined as "a life-threatening organ dysfunction caused by a dysregulated host response to infection". Although the treatment of sepsis has evolved rapidly in the last few years, the morbidity and mortality of sepsis in clinical treatment are still climbing. Sirtuins (SIRTs) are a highly conserved family of histone deacetylation involved in energy metabolism. There are many mechanisms of sepsis-induced myocardial damage, and more and more evidence show that SIRTs play a vital role in the occurrence and development of sepsis-induced myocardial damage, including the regulation of sepsis inflammation, oxidative stress and metabolic signals. This review describes our understanding of the molecular mechanisms and pathophysiology of sepsis-induced myocardial damage, with a focus on disrupted SIRTs regulation. In addition, this review also describes the research status of related therapeutic drugs, so as to provide reference for the treatment of sepsis.
... It has been reported that circulating HMGB1 has an important effect on the severity and mortality of sepsis [31][32][33]. Inflammatory cytokines are linked to the progression of sepsis by causing an excessive inflammatory response, and HMGB1 functions as a proinflammatory molecule to increase the secretion of inflammatory cytokines such as TNF-α, IL-6 and IL-1β [20]. Therefore, the regulation of HMGB1 may be a potent therapeutic method in sepsis [34]. ...
Background
Sepsis is a common severe complication in major burn victims and is characterized by a dysregulated systemic response to inflammation. YTH domain family 2 (YTHDF2), a well-studied N6-methyladenosine (m6A) reader that specifically recognizes and binds to m6A-modified transcripts to mediate their degradation, is connected to pathogenic and physiological processes in eukaryotes, but its effect on sepsis is still unknown. We aimed to discover the effects and mechanisms of YTHDF2 in sepsis.
Methods
Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blot analyses were used to measure the expression of YTHDF2, the interleukin 6 receptor (IL-6R), high-mobility group box-1 (HMGB1), Janus kinase 2 (JAK2) and signal transducer and activator of transcription 1 (STAT1) under different in vitro conditions. Enzyme-linked immunosorbent assays were utilized to evaluate the expression of HMGB1, IL-6, IL-1β and tumor necrosis factor-α. To confirm that YTHDF2 specifically targets IL-6R mRNA, RNA immunoprecipitation and dual-luciferase reporter assays were performed. Finally, we utilized a mouse model of lipopolysaccharide (LPS)-induced sepsis to verify the effects of YTHDF2 in vivo.
Results
According to our findings, YTHDF2 was expressed at a low level in peripheral blood mononuclear cells from septic mice and patients as well as in LPS-induced RAW264.7 cells. Overexpression of YTHDF2 alleviated the inflammatory response by inhibiting HMGB1 release and JAK2/STAT1 signalling in LPS-stimulated cells. Mechanistically, YTHDF2 suppressed JAK2/STAT1 signalling by directly recognizing the m6A-modified site in IL-6R and decreasing the stability of IL-6R mRNA, thereby inhibiting HMGB1 release. In vivo experiments showed that YTHDF2 played a protective role in septic mice by suppressing the IL-6R/JAK2/STAT1/HMGB1 axis.
Conclusions
In summary, these findings demonstrate that YTHDF2 plays an essential role as an inhibitor of inflammation to reduce the release of HMGB1 by inhibiting the IL-6R/JAK2/STAT1 pathway, indicating that YTHDF2 is a novel target for therapeutic interventions in sepsis.
... High mobility group protein 1 (HMGB1) levels are predictive of survival in advanced sepsis. 35,36 Lactate not only leads to the accumulation of HMGB1 in macrophages, but also inhibits the deacetylase silencing information regulator 1 (SIRT1) activity and recruits the acetylase CBP/p300, promoting lactylation modification and acetylation modification of HMGB1. 37,38 The accumulated HMGB1 is released into the blood via exosomes, and ultimately septic mice have increased mortality. ...
Introduction
As a disease that has plagued human health for decades, sepsis has so far had no specific diagnostic or therapeutic indicators. The discovery of lactylation modifications not only uncovered the deep‐rooted causes of changing between lactate level and pathophysiology and immunology of sepsis, but also reaffirmed the inevitable link between metabolic reprogramming and epigenetic reprogramming in sepsis. Lactylation modification became a potential marker for diagnosis and guiding the treatment of sepsis.
Aim
In this paper, we will summarize the discovery and regulation of lactylation modifications, discuss the study of lactylation modifications in sepsis, and evaluate their possibility and potential as diagnostic and therapeutic indicators of sepsis.
Conclusion
Lactylation modification is directly regulated by glycolysis and lactate, and inhibition of glycolytic pathway‐related enzymes can regulate the level of lactylation modification, and more importantly, lactylation modification can act on these enzymes to regulate their functions and feedback regulate the level of glycolysis, this finding provides more ideas for clinical treatment of sepsis. We use “epigenetic modification”, “glycolysis”, “lactate”, “lactylaiton” and “sepsis” as keywords and search the relevant literature through Pubmed and Web of science up to 2023.
... Similar to pathogen-associated molecular patterns (PAMPs), DAMPs are also recognized by immune-reactive cells surface pattern recognizing receptors (PRRs) [8], including Toll-like receptors (TLRs), NOD-like receptors (NLRs), C-type lectin receptors (CLRs), RIG-like receptors (RLRs), and receptor for advanced glycation end products (RAGE) [9][10][11]. Several DAMPs implicated in sepsis promotion have been recognized, including high-mobility group box protein 1 (HMGB1) [12], mitochondrial DAMPs (mitochondrial formyl peptides and mtDNA) [13], extracellular coldinducible RNA-binding protein (eCIRP) [14], histones [15], S100 calcium binding proteins A8/A9 (S100 A8/ A9) [16], heat shock proteins (HSPs) [17], interleukin-33 (IL-33) [18], and IL-1α [19]. In sepsis models, HMGB1 is actively released into the extracellular space and binds to various PRRs receptors, such as RAGE, TLR2, TLR4, and TLR9. ...
Sepsis-induced tissue and organ damage is caused by an overactive inflammatory response, immune dysfunction, and coagulation dysfunction. Danger-associated molecular pattern (DAMP) molecules play a critical role in the excessive inflammation observed in sepsis. In our previous research, we identified NMI as a new type of DAMP molecule that promotes inflammation in sepsis by binding to toll-like receptor 4 (TLR4) on macrophage surfaces, activating the NF-κB pathway, and releasing pro-inflammatory cytokines. However, it is still unknown whether NMI plays a significant role in other pathways. Our analysis of bulk and single-cell transcriptome data from the GEO database revealed a significant increase in NMI expression in neutrophils and monocytes in sepsis patients. It is likely that NMI functions through multiple receptors in sepsis, including IFNAR1, IFNAR2, TNFR1, TLR3, TLR1, IL9R, IL10RB, and TLR4. Furthermore, the correlation between NMI expression and the activation of NF-κB, MAPK, and JAK pathways, as well as the up-regulation of their downstream pro-inflammatory factors, demonstrates that NMI may exacerbate the inflammatory response through these signaling pathways. Finally, we demonstrated that STAT1 phosphorylation was enhanced in RAW cells upon stimulation with NMI, supporting the activation of JAK signaling pathway by NMI. Collectively, these findings shed new light on the functional mechanism of NMI in sepsis.
... There was a progressive but statistically nonsignificant decline in HMGB1 concentration among the survivors, while non-survivors showed an increase in HMGB1 level [14]. Similarly, another study discovered elevated HMGB1 blood levels during sepsis, however, they were unable to detect a link between HMGB1 concentration and infection severity or other cytokines [23]. ...
Sepsis is a life-threatening condition characterized by a dysregulated host response to infection. Early and accurate diagnosis of sepsis is crucial for timely intervention and improved patient outcomes. In recent years, there has been growing interest in identifying reliable biomarkers to aid in the diagnosis of sepsis. This study aims to evaluate the levels of two potential biomarkers, high-mobility group box 1 (HMGB1) and human β-defensin 3 (HBD-3), and compare their diagnostic efficacy in sepsis.
We aimed to assess HMGB-1 and HBD-3 levels in sepsis and assess the combined diagnostic validity of HMGB-1 and HBD-3. In this case-control study, the plasma concentration of HMGB-1 and HBD-3 was measured using an enzyme-linked immunosorbent assay (ELISA). Two groups, totaling 144 people, were formed; 66 patients treated in the ICU for sepsis were included in the patient group. 78 Blood donors from the Salmaniya Medical Complex Blood Bank who had no prior infection or inflammatory disease made up the Control group. The statistical computations were performed using the STATA 8® statistical software tool (StataCorp LP, College Station, TX, USA).
In patients' mean HMGB-1 levels were 2.1442 ng/ml, compared to 0.62141 ng/ml in the control group. The mean HBD-3 level was 1068.453 ng/ml in sepsis patients versus 589.935 ng/ml in controls. A significant difference between the two groups has been observed in both biomarkers (P < 0.05). The sensitivity of HMGB-1 was 75.8% and 41.3%, respectively. The sensitivity and specificity of HBD-3 were 63.6% and 93.5%, respectively.
The levels of HMGB-1 and HBD-3 between healthy and septic subjects varied significantly. HMGB-1 and HBD-3 levels in the blood tested together might accurately identify sepsis. These findings contribute to the growing body of evidence supporting the utility of biomarkers in sepsis diagnosis, and may ultimately aid in the development of more effective diagnostic strategies for sepsis management.
... Regardless of either active or passive release, extracellularly released HMGB1 has been recently identified as a delayed mediator of inflammation and is shown to be a potent inducer of TNF␣ [21]. HMGB1 has been implicated in the pathogenesis of several inflammatory disorders, including bacterial sepsis [23][24][25], arthritis [26], anorexia [27], metastatic tumor [28] and malaria [29,30], because of their ability to induce TNF␣ production from macrophages. Significantly higher levels of HMGB1 are present in inflamed synovia during arthritis [31] and in serum during sepsis [32]. ...
Mammalian homologue of high mobility group box chromatin protein (HMGB) 1 was identified and cloned from human parasites, Schistosoma mansoni and S. haematobium. Sequence analyses showed that the parasite HMGB1s has 35-40% identity to human and rodent HMGB1s, and 33% identity to Caenorhabditis elegans HMGB1. Parasite HMGB1s also contains an A box and B box domain similar to mammalian HMGB1, however, it lacks the C-terminal tail that is present in mammalian HMGB1s. Analysis of the expression of HMGB1 in various life cycle stages of S. mansoni reveal S. mansoni HMGB1 (SmHMGB1) as a stage-specific protein, expressed abundantly in egg and adult female stages and at moderate levels in skin-stage schistosomula. Significant levels of SmHMGB1 were also present in excretory secretions of egg stages. Subsequent characterization studies showed that SmHMGB1 is a potent inducer of pro-inflammatory cytokines such as TNF␣, IL-1R␣, IL-2R␣, IL-6, IL-13, IL-13R␣1, IL-15 and MIP-1␣ from mouse peritoneal macrophages. Pro-inflammatory activity, especially production of TNF␣-inducing activity, appears to be a function of the B box domain protein. This was confirmed by both real-time reverse transcription PCR and by cytokine ELISA. Thus, results presented in this study suggest that SmHMGB1 may be a key molecule in the development of host inflammatory immune responses associated with schistosomiasis.
... 28,29 Like YB-1, 12 it is found at high levels in the serum of septic humans and animals. 30,31 Furthermore, HMGB1 is a component of neutrophil extracellular traps (NETs), a meshwork of DNA, histones, and neutrophil proteins, which exhibit antimicrobial potential. NETs are induced by many pathogens but also by sterile stimuli including cytokines, immune complexes, autoantibodies, [32][33][34] and interestingly by HMGB1 itself. ...
Open-heart surgery is associated with high morbidity, with acute kidney injury (AKI) being one of the most commonly observed postoperative complications. Following open-heart surgery, in an observational study we found significantly higher numbers of blood neutrophils in a group of 13 patients with AKI compared to 25 patients without AKI (AKI: 12.9±5.4 x109 cells/L; non-AKI: 10.1±2. 9 x109 cells/L). Elevated serum levels of neutrophil extracellular trap (NETs) components, such as dsDNA, histone 3, and DNA binding protein Y-box protein (YB)-1, were found within the first 24 hours in patients who later developed AKI. We could demonstrate that NET formation and hypoxia triggered the release of YB-1 which was subsequently shown to act as a mediator of kidney tubular damage. Experimentally, in two models of AKI mimicking kidney hypoperfusion during cardiac surgery (bilateral ischemia/reperfusion (I/R) and systemic lipopolysaccharide (LPS) administration), a neutralizing YB-1 antibody was administered to mice. In both models, prophylactic YB-1 antibody administration significantly reduced the tubular damage (damage score range 1-4, the LPS model: non-specific IgG control, 0.92±0.23; anti-YB-1 0.65±0.18; and in the I/R model: non-specific IgG control 2.42±0.23; anti-YB-1 1.86±0.44). Even in a therapeutic, delayed treatment model, antagonism of YB-1 ameliorated AKI (damage score, non-specific IgG control 3.03±0.31; anti-YB-1 2.58±0.18). Thus, blocking extracellular YB-1 reduced the effects induced by hypoxia and NET formation in the kidney and significantly limited AKI suggesting that YB-1 is part of the NET formation process and an integral mediator of cross-organ effects.
... Preclinical work reveals that HMGB1 is elevated within 12-24 h of cecal ligation and puncture [12]. Human studies show that HMGB1 is elevated within 24 h of hospital presentation and remains elevated for 144 h [7,13]. These results suggest that HMGB1 is an important regulator of an early inflammatory response to an insult, including trauma and sepsis. ...
... As one of the most ubiquitous, abundant, and evolutionarily conserved transcription and growth factors in eukaryotes [26], high mobility group box 1 (HMGB1) occupies an important position in the diagnosis and treatment of HS. Consistent with multiple septic [27] or non-septic systemic inflammation [28], HMGB1 levels in HS patients were positively associated with disease severity and mortality [29]. Antithrombin III, thrombomodulin (TM), and hypothermia treatment could decrease the level of HMGB1, inhibit excessive inflammation, and improve HS-induced organ damage [30][31][32]. ...
Heat stroke (HS) is a life-threatening systemic disease characterized by an elevated core body temperature of more than 40 ℃ and subsequent multiple organ dysfunction syndrome. With the growing frequency of global heatwaves, the incidence rate of HS has increased significantly, which has caused a huge burden on people's lives and health. Liver injury is a well-documented complication of HS and usually constitutes the direct cause of patient death. In recent years, a lot of research has been carried out on the pathogenesis and treatment strategies of HS-induced liver injury. In this review, we summarized the important pathogenesis of HS-induced liver injury that has been confirmed so far. In addition to the comprehensive effect of systemic factors such as heat cytotoxicity, coagulopathy, and systemic inflammatory response syndrome, excessive hepatocyte cell pyroptosis, dysfunction of Kupffer cells, abnormal expression of heat shock protein expression, and other factors are also involved in the pathogenesis of HS-induced liver injury. Furthermore, we have also established the current therapeutic strategies for HS-induced liver injury. Our study is of great significance in promoting the understanding of the pathogenesis and treatment of HS-induced liver injury.
... HMGB1 (high mobility group protein B1), which is the first molecule identified as DAMPs, could activate innate immune cells to propagate pro-inflammatory signaling cascades and induce recruitment of neutrophils to the site of tissue injury [22][23][24]. HMGB1 levels in serum increased after LPS treatment ( Figure S4), which is consistent with that of septic patients [25,26]. This indicates that LPS treatment decreases neutrophils apoptosis but increases neutrophils infiltration; more neutrophils undergo netosis, producing NETs and aggravating the systemic inflammatory response. ...
Neutrophils play a pivotal role in innate immunity by releasing neutrophils extracellular traps (NETs). Excessive NETs are detrimental to the local tissue and further exacerbate inflammation. Protein arginine deiminases (PAD) mediate histone citrullination and NET formation that, in turn, exacerbate endotoxin shock damages. In this study, we further investigated the molecular mechanism underlying PAD and NETs in endotoxic stress in mice. The control group mice were injected with solvent, the LPS endotoxic shock group mice were intraperitoneally injected with LPS at 35 mg/kg only, while the LPS and PAD inhibitor YW3-56 treatment group mice were injected with YW3-56 at 10 mg/kg prior to the LPS injection. YW3-56 significantly prolonged the survival time of the LPS-treated mice. NETs, cfDNA, and inflammatory factors were detected by ELISA in serum, paitoneal cavity, and lung at 24 h after LPS administration. Lung injuries were detected by immunostaining, and lung tissue transcriptomes were analyzed by RNA-seq at 24 h after LPS administration. We found that YW3-56 altered neutrophil tissue homeostasis, inhibited NET formation, and significantly decreased cytokines (IL-6, TNFα and IL-1β) levels, cytokines gene expression, and lung tissue injury. In summary, NET formation inhibition offers a new avenue to manage inflammatory damages under endotoxic stress.
... Serum levels are elevated in human patients with bacteremia and sepsis-induced organ dysfunction [14]. Elevated in pneumonia-induced sepsis and associated with mortality [169]. ...
Several molecular patterns have been identified that recognize pattern recognition receptors. Pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) are commonly used terminologies to classify molecules originating from pathogen and endogenous molecules, respectively, to heighten the immune response in sepsis. Herein, we focus on a subgroup of endogenous molecules that may be detected as foreign and similarly trigger immune signaling pathways. These chromatin-associated molecules, i.e., chromatin containing nuclear DNA and histones, extracellular RNA, mitochondrial DNA, telomeric repeat-containing RNA, DNA- or RNA-binding proteins, and extracellular traps, may be newly classified as chromatin-associated molecular patterns (CAMPs). Herein, we review the release of CAMPs from cells, their mechanism of action and downstream immune signaling pathways, and targeted therapeutic approaches to mitigate inflammation and tissue injury in inflammation and sepsis.
... In an animal model that attempts to mimic the massive release of bacterial LPS sometimes observed in clinical sepsis [133], Peek et al., in their article published in Pharmaceuticals, focused on the High Mobility Group Box-1 Protein (HMGB-1), a nuclear DNA-binding protein that alters the structure of chromatin, but which can serve as a danger-associated molecular pattern or alarmin and mimic pro-inflammatory cytokine activity when present in the extracellular space [134]. These authors relate studies showing that circulating concentrations of HMGB-1 are increased during severe clinical sepsis and septic shock [135] and several hours after the peripheral administration of high doses of LPS to rodents [136]. Interestingly, oxidative stress favors the formation of disulfide HMGB-1, which can, just like bacterial LPS, activate the toll-like receptor 4 (TLR4) [134]. ...
In spite of the brain-protecting tissues of the skull, meninges, and blood-brain barrier, some forms of injury to or infection of the CNS can give rise to cerebral cytokine production and action and result in drastic changes in brain function and behavior. Interestingly, peripheral infection-induced systemic inflammation can also be accompanied by increased cerebral cytokine production. Furthermore, it has been recently proposed that some forms of psychological stress may have similar CNS effects. Different conditions of cerebral cytokine production and action will be reviewed here against the background of neuroinflammation. Within this context, it is important to both deepen our understanding along already taken paths as well as to explore new ways in which neural functioning can be modified by cytokines. This, in turn, should enable us to put forward different modes of cerebral cytokine production and action in relation to distinct forms of neuroinflammation.
... Later, however, the release of DAMPs was recognized as the critical event in mortality in sepsis. Clinically, the severity of sepsis correlates with the level of some DAMPs, such as HMGB1 [79], CIRP [80], histones [47], HSP70 [81], and circulating plasma DNA [82]. Mitochondrial DAMPs [83] and extracellular ATP [84] were also suggested to contribute to sepsis mortality. ...
In humans, over-activation of innate immunity in response to viral or bacterial infections often causes severe illness and death. Furthermore, similar mechanisms related to innate immunity can cause pathogenesis and death in sepsis, massive trauma (including surgery and burns), ischemia/reperfusion, some toxic lesions, and viral infections including COVID-19. Based on the reviewed observations, we suggest that such severe outcomes may be manifestations of a controlled suicidal strategy protecting the entire population from the spread of pathogens and from dangerous pathologies rather than an aberrant hyperstimulation of defense responses. We argue that innate immunity may be involved in the implementation of an altruistic programmed death of an organism aimed at increasing the well-being of the whole community. We discuss possible ways to suppress this atavistic program by interfering with innate immunity and suggest that combating this program should be a major goal of future medicine.
... Elevation of HMGB1 was detected considerably later than secretion of acute-phase cytokines (such as TNF and IL-1) and reach a persistent plateau at 16-32 h in LPS-induced endotoxemia models and sepsis patients. 165,167 Besides, remarkable elevation of HMGB1 is observed in severe sepsis patients and correlate to disease progression. 168,169 In resting cells, HMGB1 was found anchored to nucleus and stabilized by chromatins. ...
Sepsis is defined as life-threatening organ dysfunction caused by dysregulated host systemic inflammatory and immune response to infection. Over decades, advanced understanding of host–microorganism interaction has gradually unmasked the genuine nature of sepsis, guiding toward new definition and novel therapeutic approaches. Diverse clinical manifestations and outcomes among infectious patients have suggested the heterogeneity of immunopathology, while systemic inflammatory responses and deteriorating organ function observed in critically ill patients imply the extensively hyperactivated cascades by the host defense system. From focusing on microorganism pathogenicity, research interests have turned toward the molecular basis of host responses. Though progress has been made regarding recognition and management of clinical sepsis, incidence and mortality rate remain high. Furthermore, clinical trials of therapeutics have failed to obtain promising results. As far as we know, there was no systematic review addressing sepsis-related molecular signaling pathways and intervention therapy in literature. Increasing studies have succeeded to confirm novel functions of involved signaling pathways and comment on efficacy of intervention therapies amid sepsis. However, few of these studies attempt to elucidate the underlining mechanism in progression of sepsis, while other failed to integrate preliminary findings and describe in a broader view. This review focuses on the important signaling pathways, potential molecular mechanism, and pathway-associated therapy in sepsis. Host-derived molecules interacting with activated cells possess pivotal role for sepsis pathogenesis by dynamic regulation of signaling pathways. Cross-talk and functions of these molecules are also discussed in detail. Lastly, potential novel therapeutic strategies precisely targeting on signaling pathways and molecules are mentioned.
... Previous studies about the pathogenesis of inflammatory diseases like sepsis have only highlighted the early inflammatory mediators in the course of sepsis (Tracey et al., 1987;Tracey & Lowry, 1990). However, clinical trials of drugs with inhibitory effects on early cytokines such as TNF-α and IL-1β failed to improve survival in septic patients (Abraham et al., 1995;Sundén-Cullberg et al., 2005). Unlike the early release and disappearance of TNF-α and IL-1β, the serum concentrations of HMGB1 increase within 8 to 32 hours and maintain high levels for at least 96 hours (Wang et al., 2011). ...
Abstract Acanthopanax gracilistylus W.W.Smith (AGS) is an traditional Chinese medicine and its leaves that have rich biological activities has been long used as a fresh vegetable in Chinese folk. There are two lupane-type triterpenoids, 3α,11α-dihydroxy-23-oxo-lup-20(29)-en-28-oic acid (1) and 3α,11α,23-trihydroxy-lup-20(29)-en-28-oic acid (2), were isolated as the active constituents from leaves of AGS. However, the anti-inflammatory effects and potential mechanisms of 1 and 2 on LPS-induced RAW264.7 Macrophages have not been evaluated. In this study, the results shown that compounds 1 and 2 reduced the levels of early pro-inflammatory cytokines TNF-α, IL-1β, the secretion of late pro-inflammatory cytokine HMGB1, as well as the activation of transcription factor NF-κB in RAW 264.7 macrophages induced by LPS. In conclusion, two lupane-type triterpenes (1 and 2) have anti-inflammatory activities in LPS-induced RAW264.7 cells through inhibiting expression of proinflammatory cytokines and NF‐κB activation and could be potentially used in treatment of inflammatory-related diseases in the future.
... Serum HMGB1 level is low in healthy humans and significantly elevated in different pathological states. One study in patients with sepsis showed higher plasma concentration in nonsurvivors than survivors (11), but the results were contradictory in another study (12). Burn injury is associated with severe hypovolemia caused by excessive edema formation. ...
High-mobility group box protein 1 (HMGB1) is a nuclear protein that may be released actively from monocytes and macrophages or passively from necrotic or damaged cells. Several experimental data suggest that burn injury is accompanied by elevated plasma HMGB, but there are only few data available about its changes in burned patients. The aim of this study was to follow the time course and the prognostic value of plasma HMGB1 and cytokine changes in patients with severe burn injury affecting more than 10% of body surface area (n = 26). Blood samples were taken on admission and on the following 5 days. Plasma HMGB1 concentration was measured by the enzyme-linked immunosorbent assay method, whereas IL-6, IL-8, and IL-10 were assayed by the cytometric bead array kit. The HMGB1 and IL-10 concentrations were elevated on admission and gradually decreased thereafter. Significant differences were observed between survivors and nonsurvivors in HMGB1 (P G 0.01) and IL-10 (P G 0.001) concentrations on admission with higher levels in nonsurvivors. IL-6 and IL-8 started to increase markedly from day 2. Positive correlation (r = 0.669, P G 0.01) was found between burned body surface and HMGB1 on admission. Receiver operating characteristic analysis of data on admission showed that at a level of 16 ng/mL, HMGB1 indicated lethality, with 75.0% sensitivity and 85.7% specificity. Using the cutoff level of 14 pg/mL, IL-10 predicted intensive care unit mortality, with 85.7% sensitivity and 84.2% specificity. Very early HMGB1 and IL-10 release may have an important impact on the immune function of patients after burn trauma.
... A protein frequently upregulated in hypoxic conditions is high-mobility group box 1 (HMGB1) [23,24]. HMGB1 is a conserved evolutionarily DNA-binding nuclear protein that has been represented as a damageassociated molecular pattern (DAMP) protein involved in several disease states, including sepsis [25], arthritis [26], and cancer [27]. Tumor cells can release HMGB1 into the local microenvironment, where HMGB1 interacts with several receptors, such as toll-like receptor 2 (TLR-2), TLR-4, TLR-9, and the receptor for advanced glycation end products (RAGE), which can lead to tumor cell survival, proliferation, and angiogenesis [3,28,29]. ...
Several B-cell subsets with distinct functions and polarized cytokine profiles that extend beyond antibody production have been reported in different cancers. Here we have demonstrated that proliferating B cells were predominantly found in the peritumoral region of esophageal squamous cell carcinoma (ESCC). These B cells were enriched in tumor nests with high expression of high-mobility group box 1 (HMGB1). High densities of peritumoral proliferating B cells and concomitantly high intratumoral HMGB1 expression showed improved prognostic significance, surpassing prognostic stratification of ESCC patients based on HMGB1 positivity alone. This striking association led us to set up models to test whether cancer-derived HMGB1 could shape tumor microenvironment via modulation on B cells. Overexpression of HMGB1 in ESCC cell lines (KYSE510 and EC18) enhanced proliferation and migration of B cells. Transcriptomic analysis showed that migratory B cells exhibited high enrichment of proangiogenic genes. VEGF expression in proliferating B cells was induced upon co-culture of HMGB1-overexpressing tumor cells and B cells. Secretome array profiling of conditioned media (CM) from the co-culture revealed rich expression of proangiogenic proteins. Consequently, incubation of human umbilical vein endothelial cells with CM promoted angiogenesis in tube formation and migration assays. HMGB1 inhibitor, glycyrrhizin, abolishes all the observed proangiogenic phenotypes. Finally, co-injection of B cells and CM with HMGB1-overexpressing tumor cells, but not with glycyrrhizin, significantly enhanced tumor growth associated with increased microvascular density in ESCC xenograft mice model. Our results indicate that cancer-derived HMGB1 elevates angiogenesis in ESCC by shifting the balance toward proangiogenic signals in proliferating B cells.
... TNFa is a necessary and sufficient mediator of local and systemic inflammation with regards to burns (44)(45)(46)(47). TNFa enhances and prolongs an inflammatory response by activating other cells to release proinflammatory cytokines such as IL-1 and HMGB1 (48). IL-1 is released by macrophages, lymphocytes, and monocytes during infection, injury and inflammation (49). ...
Severe burn-induced inflammation and subsequent hypermetabolic response can lead to profound infection and sepsis, resulting in multiple organ failure and high mortality risk in patients. This represents an extremely challenging issue for clinicians as sepsis is the leading cause of mortality in burn patients. Since hyperinflammation and immune dysfunction are a result of an immune imbalance, restoring these conditions seem to have promising benefits for burn patients. A key network that modulates the immune balance is the central nervous system (CNS)-spleen axis, which coordinates multiple signaling pathways, including sympathetic and parasympathetic pathways. Modulating inflammation is a key strategy that researchers use to understand neuroimmunomodulation in other hyperinflammatory disease models and modulating the CNS-spleen axis has led to improved clinical outcomes in patients. As the immune balance is paramount for recovery in burn-induced sepsis and patients with hyperinflammatory conditions, it appears that severe burn injuries substantially alter this CNS-spleen axis. Therefore, it is essential to address and discuss the potential therapeutic techniques that target the CNS-spleen axis that aim to restore homeostasis in burn patients. To understand this in detail, we have conducted a systematic review to explore the role of the CNS-spleen axis and its impact on immunomodulation concerning the burn-induced hypermetabolic response and associated sepsis complications. Furthermore, this thorough review explores the role of the spleen, CNS-spleen axis in the ebb and flow phases following a severe burn, how this axis induces metabolic factors and immune dysfunction, and therapeutic techniques and chemical interventions that restore the immune balance via neuroimmunomodulation.
... HMGB1 is a ubiquitous nuclear protein that can be released by activated macrophages to orchestrate inflammatory responses [4][5][6]. Clinical evidence has revealed that the levels of circulating HMGB1 are markedly elevated and positively correlated with sepsis severity and mortality [7][8][9]. Notably, a recent single-institution study, including 218 critically ill patients (145 with sepsis and 73 without sepsis), revealed that blood HMGB1 levels positively correlated with blood lactate levels (r = 0.144, P = 0.035), suggesting that lactate could regulate HMGB1 release in sepsis [10]. Previous studies have shown that post-translational modification (i.e., acetylation, phosphorylation, and methylation) of HMGB1 at the region close to or within the nuclear localization sequences (NLSs) could induce its translocation to the cytoplasm, leading to subsequent release of HMGB1 during inflammation [11][12][13]. ...
High circulating levels of lactate and high mobility group box-1 (HMGB1) are associated with the severity and mortality of sepsis. However, it is unclear whether lactate could promote HMGB1 release during sepsis. The present study demonstrated a novel role of lactate in HMGB1 lactylation and acetylation in macrophages during polymicrobial sepsis. We found that macrophages can uptake extracellular lactate via monocarboxylate transporters (MCTs) to promote HMGB1 lactylation via a p300/CBP-dependent mechanism. We also observed that lactate stimulates HMGB1 acetylation by Hippo/YAP-mediated suppression of deacetylase SIRT1 and β-arrestin2-mediated recruitment of acetylases p300/CBP to the nucleus via G protein-coupled receptor 81 (GPR81). The lactylated/acetylated HMGB1 is released from macrophages via exosome secretion which increases endothelium permeability. In vivo reduction of lactate production and/or inhibition of GPR81-mediated signaling decreases circulating exosomal HMGB1 levels and improves survival outcome in polymicrobial sepsis. Our results provide the basis for targeting lactate/lactate-associated signaling to combat sepsis.
Thymocyte selection–associated high-mobility group box (TOX) is a transcription factor that is crucial for T cell exhaustion during chronic antigenic stimulation, but its role in inflammation is poorly understood. Here, we report that TOX extracellularly mediates drastic inflammation upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by binding to the cell surface receptor for advanced glycation end-products (RAGE). In various diseases, including COVID-19, TOX release was highly detectable in association with disease severity, contributing to lung fibroproliferative acute respiratory distress syndrome (ARDS). Recombinant TOX-induced blood vessel rupture, similar to a clinical signature in patients experiencing a cytokine storm, further exacerbating respiratory function impairment. In contrast, disruption of TOX function by a neutralizing antibody and genetic removal of RAGE diminished TOX-mediated deleterious effects. Altogether, our results suggest an insight into TOX function as an inflammatory mediator and propose the TOX–RAGE axis as a potential target for treating severe patients with pulmonary infection and mitigating lung fibroproliferative ARDS.
Sepsis is a serious organ dysfunction caused by a dysregulated immune host reaction to a pathogen. The innate immunity is programmed to react immediately to conserved molecules, released by the pathogens (PAMPs), and the host (DAMPs). We aimed to review the molecular mechanisms of the early phases of sepsis, focusing on PAMPs, DAMPs, and their related pathways, to identify potential biomarkers. We included studies published in English and searched on PubMed® and Cochrane®. After a detailed discussion on the actual knowledge of PAMPs/DAMPs, we analyzed their role in the different organs affected by sepsis, trying to elucidate the molecular basis of some of the most-used prognostic scores for sepsis. Furthermore, we described a chronological trend for the release of PAMPs/DAMPs that may be useful to identify different subsets of septic patients, who may benefit from targeted therapies. These findings are preliminary since these pathways seem to be strongly influenced by the peculiar characteristics of different pathogens and host features. Due to these reasons, while initial findings are promising, additional studies are necessary to clarify the potential involvement of these molecular patterns in the natural evolution of sepsis and to facilitate their transition into the clinical setting.
High mobility group box-1 protein (HMGB-1); sepsisin son fazında doğal bağışıklık hücreleri tarafından aktif olarak salgılanan ve/veya yaralı veya hasarlı hücreler tarafından pasif olarak salınan güçlü bir pro-inflamatuar sitokin olarak görev yapar. Bu nedenle, HMGB1'in serum ve doku seviyeleri enfeksiyon sırasında, özellikle sepsis sırasında yükselir. Bu çalışmada, yenidoğan sepsisinde HMGB1 seviyelerini ve septik şok ve ölümle ilişkisinin değerlendirilmesi amaçlandı. Klinik veya kanıtlanmış sepsis tanısı olan 53 yenidoğan çalışmaya dahil edildi. Enfeksiyon semptomu veya bulgusu olmayan ve rutin YYBÜ bakımı alan doğum sonrası yaşı eşleştirilmiş elli yedi yenidoğan kontrol olarak alındı. On iki hastada kanıtlanmış sepsis, 6 hastada septik şok vardı. Beş septik bebek kaybedildi. Sepsisli yenidoğanlarda HMGB1 düzeyleri kontrollere kıyasla daha yüksekti; septik şoklu hastalarda septik şok olmayanlara kıyasla daha yüksek HMGB1 düzeyleri vardı (p=0,002). Hayatta kalmayanların hayatta kalanlara kıyasla daha yüksek HMGB1 seviyelerine sahip olmasına rağmen, bu istatistiksel olarak anlamlı değildi (p=0,086). HMGB1 düzeyleri septik şoku olmayan hastalarda tanıdan üç gün sonra önemli ölçüde düşerken (p=0,014) septik şok gelişen hastalarda yüksek kaldı (p=0,465). CRP ile HMGB1 arasında pozitif bir korelasyon saptandı (p=0,008, r=0,252). HMGB1, sepsisli hastaları septik olmayan gruptan ayırmak için hassas bir belirteçtir. Enflamatuar belirteçler grubuna HMGB1'in eklenmesi, sepsis tanısına kıyasla ciddi sepsisli hastaların tespitinde faydalı olabilir.
Sepsis is a hyper-heterogeneous syndrome in which the systemic inflammatory response persists throughout the course of the disease and the inflammatory and immune responses are dynamically altered at different pathogenic stages. Gasdermins (GSDMs) proteins are pore-forming executors in the membrane, subsequently mediating the release of pro-inflammatory mediators and inflammatory cell death. With the increasing research on GSDMs proteins and sepsis, it is believed that GSDMs protein are one of the most promising therapeutic targets in sepsis in the future. A more comprehensive and in-depth understanding of the functions of GSDMs proteins in sepsis is important to alleviate the multi-organ dysfunction and reduce sepsis-induced mortality. In this review, we focus on the function of GSDMs proteins, the molecular mechanism of GSDMs involved in sepsis, and the regulatory mechanism of GSDMs-mediated signaling pathways, aiming to provide novel ideas and therapeutic strategies for the diagnosis and treatment of sepsis.
Sepsis induces neuroinflammation, BBB disruption, cerebral hypoxia, neuronal mitochondrial dysfunction, and cell death causing sepsis‐associated encephalopathy (SAE). These pathological consequences lead to short‐ and long‐term neurobehavioural deficits. Till now there is no specific treatment that directly improves SAE and its associated behavioural impairments. In this review, we discuss the underlying mechanisms of sepsis‐induced brain injury with a focus on the latest progress regarding neuroprotective effects of SIRT1 (silent mating type information regulation‐2 homologue‐1). SIRT1 is an NAD ⁺ ‐dependent class III protein deacetylase. It is able to modulate multiple downstream signals (including NF‐κB, HMGB, AMPK, PGC1α and FoxO), which are involved in the development of SAE by its deacetylation activity. There are multiple recent studies showing the neuroprotective effects of SIRT1 in neuroinflammation related diseases. The proposed neuroprotective action of SIRT1 is meant to bring a promising therapeutic strategy for managing SAE and ameliorating its related behavioural deficits.
Mortality in acute infections is mostly associated with sepsis, defined as 'life-threatening organ dysfunction caused by a dysregulated host response to infection'. It remains challenging to identify the patients with increased mortality risk due to the high heterogeneity in the dysregulated host immune response and disease progression. Biomarkers reflecting different pathways involved in the inflammatory response might improve prediction of mortality risk (prognostic enrichment) among patients with acute infections by reducing heterogeneity of the host response, as well as suggest novel strategies for patient stratification and treatment (predictive enrichment) through precision medicine approaches. The predictive value of inflammatory biomarkers has been extensively investigated in bacterial infections and the recent COVID-19 pandemic caused an increased interest in inflammatory biomarkers in this viral infection. However, limited research investigated whether the prognostic potential of these biomarkers differs between bacterial and viral infections. In this narrative review, we provide an overview of the value of various inflammatory biomarkers for the prediction of mortality in bacterial and viral infections.
Objectives:
Damage associated molecular patterns (DAMPs) levels are associated with sepsis severity and prognosis. Histone and high mobility group box 1 (HMGB1) levels are also potential indicators of prognosis. We investigated the relationship between serum histone H3 and HMGB1 levels and the illness severity score and prognosis in postoperative patients.
Methods:
Postoperative serum histone H3 and HMGB1 levels in 39 intensive care unit (ICU) patients treated at our institution were measured. The correlation between peak histone H3 and HMGB1 levels in each patient and clinical data (age, sex, surgical time, length of ICU stay, and survival after ICU discharge), which also included the patients' illness severity score, was examined.
Results:
Histone H3 but not HMGB1 levels were positively correlated with surgical time, the Sequential Organ Failure Assessment score, the Japanese Association for Acute Medicine acute phase disseminated intravascular coagulation diagnosis score, and the length of ICU stay. Both histone H3 and HMGB1 levels were negatively correlated with age. However, survival post-ICU discharge was not correlated with histone H3 or HMGB1 levels.
Conclusions:
Histone H3 levels are correlated with severity scores and the length of ICU stay. Serum histone H3 and HMGB1 levels are elevated postoperatively. These DAMPs, however, are not prognostic indicators in postoperative ICU patients.
IntroductionWe investigated the efficiency of high mobility group box-1 protein (HMGB-1) in differentiation of asymptomatic knee prosthesis, and periprosthetic joint infection and aseptic loosening causing painful knee prosthesis.Materials and Methods
The data of patients who consulted our clinic for checking after total knee arthroplasty surgery were recorded prospectively. Blood levels of CRP, ESR, WBC, and HMGB-1 were recorded. Patients whose examination and routine tests were within normal limits comprised group I, asymptomatic total knee arthroplasty (ATKA). Painful patients with abnormal test results underwent three phase bone scintigraphy for further investigation Patients with periprosthetic joint infection (PJI) and aseptic loosening (AL) according to scintigraphy comprised group II and group III, respectively. The mean values of HMGB-1 and cut-off values according to the groups and their correlations with other inflammatory parameters were determined.ResultsSeventy-three patients were included in the study. Significant differences were observed in three groups, in terms of CRP, ESR, WBC, and HMGB-1. The cut-off value of HMGB-1 was determined as 15.16 ng/ml between ATKA and PJI, 16.92 ng/ml between ATKA and AL, and 27.87 ng/ml between PJI and AL, respectively. Accordingly, the sensitivity, and specificity of HMGB-1 in differentiation of ATKA and PJI were 91%, 88%, and in differentiation of ATKA and AL were 91%, 96%, and in differentiation of PJI and AL were 81%, 73%, respectively.ConclusionHMGB-1 may be utilized as an additional blood test in the differential diagnosis of problematic knee prosthesis patients.
Protein posttranslational modification (PTM) is a biochemical mechanism benefitting cellular adaptation to dynamic intracellular and environmental conditions. Recently, several acylation marks have been identified as new protein PTMs occurring on specific lysine residues in mammalian cells: isobutyrylation, methacrylation, benzoylation, isonicotinylation, and lactylation. These acylation marks were initially discovered to occur on nucleosomal histones, but they potentially occur as prevalent biomarkers on non-histone proteins as well. The existence of these PTMs is a downstream consequence of metabolism and demonstrates the intimate crosstalk between active cellular metabolites and regulation of protein function. Emerging evidence indicates that these acylation marks on histones affect DNA transcription and are functionally distinct from the well-studied lysine acetylation. Herein, we discuss enzymatic regulation and metabolic etiology of these acylations, 'reader' proteins that recognize different acylations, and their possible physiological and pathological functions. Several of these modifications correlate with other well-studied acylations and fine-tune the regulation of gene expression. Overall, findings of these acylation marks reveal new molecular links between metabolism and epigenetics and open up many questions for future investigation. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC.
This fourth chapter of the “Infection” Part begins with an overview of reports on the various subclasses of activating damage-associated molecular patterns (DAMPs) and suppressing damage-associated molecular patterns (SAMPs) that—in concert with microbe-associated molecular patterns (MAMPs)—drive controlled proinflammatory, inflammation-resolving, and uncontrolled hyperinflammatory/“hyperresolving” and nonresolving/persisting responses in bacterial, viral, and fungal infections. Following, the hyperinflammatory response triggered by the emission of DAMPs in excess and the inflammation-hyperresolving response driven by counterbalancing SAMPs are highlighted by presenting three clinical examples: (1) severe virus-induced pneumonia-related acute respiratory distress syndrome (ARDS), (2) life-threatening bacterium-induced sepsis, and (3) devastating protozoan-induced malaria. In ARDS, the focus is on the pathogenetic involvement of DAMPs and SAMPs in its typical hallmarks: the cytokine storm, an immunosuppressive state, and disseminated intravascular coagulation. In sepsis, the same scenario is again highlighted: the pathogenetic implication of various subclasses of DAMPs and SAMPs in the characteristic hallmarks of the disease that are very similar to those of ARDS. Both sections, the one on ARDS and the one on sepsis, end with a proposal to harness DAMPs and SAMPs as (1) biomarkers in diagnosis and prognosis and (2) novel therapeutic targets or therapeutics for the treatment and prophylaxis of these life-threatening diseases. In malaria, the focus is directed on the special DAMPs involved in the pathogenesis of this disease, which include, besides the prototypical HMGB1, specific molecules such as heme, hemozoin, and uric acid. The chapter ends by delineating a narrative summary model on DAMP/SAMP-dependent clinical outcomes of infectious diseases by tentatively proposing an integration of various DAMP/SAMP-driven immune responses in different clinical courses of infections (exemplified in part by COVID-19 pneumonia) and predicting that the exploitation of DAMPs and SAMPs as biomarkers, therapeutic targets, and therapeutics will improve the outcome of infectious diseases in the near future.
Cardiorenal syndrome (CRS) atau sindroma kardiorenal merupakan suatu kondisi dimana terjadi penyakit ginjal dan penyakit jantung secara bersamaan yang progresifitasnya terjadi dengan cepat. Pada kasus dimana penyakit jantung merupakan penyakit primer, yang terjadi adalah gangguan dinamika kardioavaskular, aktivasi neurohormonal dan faktor inflamasi yang terlibat dalam awal-mulanya perburukan fungsi ginjal dan penyakit ginjal yang progresif.Sepsis adalah “respons sistemik terhadap infeksi yang telah terdokumenetasi atau masih dicurigai dan terjadi disfungsi satu organ”; terdiri dari hipotermia/hipertermia, takikardia, takipnea, infeksi, dan disfungsi organ akhir akibat hipoperfusi. Sepsis yang lebih modern didasari konsep SIRS, sebuah istilah yang mendeskripsikan kompleks imun sebagai respons infeksi dan digunakan untuk menggambarkan ciri klinis yang berkaitan dengan respons tersebut. Penggunaan klinis SIRS menggambarkan kekacauan laju nafas, frekuensi denyut jantung, temperature, dan jumlah leukosit. Jika ada 2 dari 4 kriteria di bawah ini, SIRS bisa ditegakkan: nafas > 20 kali per menit atau PaCo2 <32 mmHg, frekuensi nadi >90 kali per menit, suhu >38o C atau <36o C, dan leukosit >12,000/mm3 atau <4,000/mm3.CRS sepsis adalah disfungsi renal dan kardiak yang terjadi bersamaan dalam sebuah kondisi sistemik primer yang mempengaruhi kedua organ. “Tuntutan iskemik” jantung didasarkan pada alasan meningkatnya kebutuhan oksigen berkaitan dengan respons sepsis (misalnya takikardia, peningkatan curah jantung) yang mengarah kepada cedera iskemik. Disfungsi renal dapat dilihat selama sepsis berat dan merupakan bagian dari gambaran klinis syok septik dan kegagalan multi organ.
Extracellular cold-inducible RNA binding protein (eCIRP) is an inflammatory mediator that causes inflammation and tissue injury in sepsis. Gasdermin D (GSDMD) is a protein that, when cleaved, forms pores in the cell membrane, releasing intracellular contents into the extracellular milieu to exacerbate inflammation. We hypothesize that eCIRP is released actively from viable macrophages via GSDMD pores. We found that LPS induced eCIRP secretion from macrophages into the extracellular space. LPS significantly increased the expression of caspase-11 and cleavage of the GSDMD, as evidenced by increased N-terminal GSDMD expression in RAW 264.7 cells and mouse primary peritoneal macrophages. GSDMD inhibitor disulfiram decreased eCIRP release in vitro. Treatment with glycine to prevent pyroptosis-induced cell lysis did not significantly decrease eCIRP release from LPS-treated macrophages, indicating that eCIRP was actively released and was independent of pyroptosis. Downregulation of GSDMD gene expression by siRNA transfection suppressed eCIRP release in vitro after LPS stimulation. Moreover, GSDMD-/- peritoneal macrophages and mice had decreased levels of eCIRP in the culture supernatants and in blood treated with LPS in vitro and in vivo, respectively. GSDMD inhibitor disulfiram inhibited serum levels of eCIRP in endotoxemia and cecal ligation and puncture-induced sepsis. We conclude that eCIRP release from living macrophages is mediated through GSDMD pores, suggesting that targeting GSDMD could be a novel and potential therapeutic approach to inhibit eCIRP-mediated inflammation in sepsis.
Sepsis susceptibility is significantly increased in patients with intracerebral hemorrhage (ICH), owing to immunosuppression and intestinal microbiota dysbiosis. To date, ICH with sepsis occurrence is still difficult for clinicians to deal with, and the mortality, as well as long-term cognitive disability, is still increasing. Actually, intracerebral hemorrhage and sepsis are mutually exacerbated via similar pathophysiological mechanisms, mainly consisting of systemic inflammation and circulatory dysfunction. The main consequence of these two processes is neural dysfunction and multiple organ damages, notably, via oxidative stress and neurotoxic mediation under the mediation of central nervous system activation and blood-brain barrier disruption. Besides, the comorbidity-induced multiple organ damages will produce numerous damage-associated molecular patterns and consequently exacerbate the severity of the disease. At present, the prospective views are about operating artificial restriction for the peripheral immune system and achieving cross-tolerance among organs via altering immune cell composition to reduce inflammatory damage.
Objective
Lupus pleuritis is the most common pulmonary manifestation of systemic lupus erythematosus (SLE). We aimed to compare various biomarkers in discriminating between pleural effusions due to lupus pleuritis and other aetiologies.
Methods
We determined in 59 patients (16 patients with SLE and 43 patients without SLE) pleural fluid levels of high-mobility group box 1, soluble receptor for advanced glycation end products (sRAGE), adenosine deaminase (ADA), interleukin (IL) 17A, tumour necrosis factor-α, antinuclear antibodies (ANA), and complements C3 and C4.
Results
We found significant differences in the pleural fluid level of sRAGE, ADA, IL-17A, C3 and C4, and in the proportion of ANA positivity, among lupus pleuritis and other groups with pleural effusion. Specifically, ANA positivity (titre ≥1: 80) achieved a high sensitivity of 91%, specificity of 83% and negative predictive value (NPV) of 97% in discriminating lupus pleuritis from non-lupus pleural effusion. A parallel combination of the level of C3 (<24 mg/dL) and C4 (<3 mg/dL) achieved a sensitivity of 82%, specificity of 89% and NPV of 93% in discriminating lupus pleuritis from non-lupus exudative pleural effusion.
Conclusions
In conclusion, ANA, C3 and C4 in pleural fluid are useful in discriminating lupus pleuritis from pleural effusion due to other aetiologies with high NPV.
High mobility group box-1 protein (HMGB1) is a typical Damage-Associated Molecular Patterns (DAMPs) released in response to cellular inflammation. The pentacyclic triterpenes (PTs) are considered to be the natural inhibitors against HMGB1-related inflammation. To explore new lead compounds of PTs as anti-inflammatory agents, biotransformation of four PTs by Streptomyces olivaceus CICC 23628 was investigated in this study. As a result, thirteen unique 3,4-seco-triterpenes metabolites were isolated and twelve of them were first identified and reported. Structures of metabolites were determined based on HR-ESI-MS, 1D/2D NMR, and single-crystal X-ray diffraction. Furthermore, all compounds were subjected to the bioassay on the model of HMGB1-stimulated RAW 264.7 cells to evaluate their anti-inflammatory activity through nitric oxide (NO) inhibition activity. Compounds 3b (3,4-seco-olean-12-en-4,21α,22β,24-tetrahydroxy-ol-3-oic acid) and 2b (3,4-seco-olean-12-en-4,21β,22β,24,29-pentahydroxy-ol-3-oic acid) exhibited NO inhibitory activity with IC50 values of 15.94 μM and 36.00 μM, respectively. Thus, indicating their potential as HMGB1 inhibitors and in developing potent anti-inflammatory agents. This work provides an operationally simple, efficient method for the rapid diversification of the PTs scaffold for a variety of distinctive 3,4-seco-triterpenes to facilitate the discovery of potential anti-inflammatory compounds.
SARS-COV-2 explores every possible vulnerability in human body and uses it against the host. To treat this SARS-COV-2 induced COVID-19, we should target the multiple factors virus is targeting and use the drugs in a strategical way. This approach can save the patients from severe state of illness and damage associated with the disease.
The noncanonical inflammasome, comprising inflammatory caspases 4, 5, or 11, monitors the cytosol for bacterial lipopolysaccharide (LPS). Intracellular LPS-elicited autoproteolysis of these inflammatory caspases leads to the cleavage of the pore-forming protein gasdermin D (GSDMD). GSDMD pore formation induces a lytic form of cell death known as pyroptosis and the release of inflammatory cytokines and DAMPs, thereby promoting inflammation. The noncanonical inflammasome-dependent innate sensing of cytosolic LPS plays important roles in bacterial infections and sepsis pathogenesis. Exciting studies in the recent past have significantly furthered our understanding of the biochemical and structural basis of the caspase-4/11 activation of GSDMD, caspase-4/11's substrate specificity, and the biological consequences of noncanonical inflammasome activation of GSDMD. This review will discuss these recent advances and highlight the remaining gaps in our understanding of the noncanonical inflammasome and pyroptosis.
Sepsis is a continuing problem in modern healthcare, with a relatively high prevalence, and a significant mortality rate worldwide. Currently, no specific anti-sepsis treatment exists despite decades of research on developing potential therapies. Annexins are molecules that show efficacy in preclinical models of sepsis but have not been investigated as a potential therapy in patients with sepsis. Human annexins play important roles in cell membrane dynamics, as well as mediation of systemic effects. Most notably, annexins are highly involved in anti-inflammatory processes, adaptive immunity, modulation of coagulation and fibrinolysis, as well as protective shielding of cells from phagocytosis. These discoveries led to the development of analogous peptides which mimic their physiological function, and investigation into the potential of using the annexins and their analogous peptides as therapeutic agents in conditions where inflammation and coagulation play a large role in the pathophysiology. In numerous studies, treatment with recombinant human annexins and annexin analogue peptides have consistently found positive outcomes in animal models of sepsis, myocardial infarction, and ischemia reperfusion injury. Annexins A1 and A5 improve organ function and reduce mortality in animal sepsis models, inhibit inflammatory processes, reduce inflammatory mediator release, and protect against ischemic injury. The mechanisms of action and demonstrated efficacy of annexins in animal models support development of annexins and their analogues for the treatment of sepsis. The effects of annexin A5 on inflammation and platelet activation may be particularly beneficial in disease caused by SARS-CoV-2 infection. Safety and efficacy of recombinant human annexin A5 are currently being studied in clinical trials in sepsis and severe COVID-19 patients.
Background
The role of blood high mobility group box-1 (HMGB-1) protein in predicting mortality of sepsis remains controversial.
Objective
Here we conducted a meta-analysis to seek evidence for the association between blood HMGB-1 concentrations and mortality in patients with sepsis.
Methods
Eligible studies were identified by a comprehensive search of six digital databases, supplemented by a manual search of related references. Standardized mean differences (SMDs) and corresponding 95% confidence intervals (CIs) were calculated as effect estimates.
Results
A total of eighteen studies, covering 1163 patients with sepsis, were included. Compared with survival groups of sepsis, non-survival groups had significantly higher blood HMGB-1 concentrations at enrollment (SMD: 0.45, 95% CI: 0.21–0.69). Subgroup analyses showed that no significant differences were found between two groups among patients with more severe sepsis (SMD: 0.18, 95% CI: -0.02–0.38). A significant association between initial HMGB-1 levels and ≤30-day mortality remained (SMD: 0.43, 95% CI: 0.09–0.78). Besides, HMGB-1 levels were observed to be more significantly higher in non-survival groups after the third day of admission (SMD: 1.33, 95% CI: 1.05–1.62) but two groups attained comparable HMGB-1 levels on day 7 (SMD: 1.01, 95% CI: -0.31–2.33).
Conclusions
Initial high blood HMGB-1 levels are significantly associated with short-term (≤30 days) mortality of patients with sepsis, and the association may be affected by the severity of sepsis. Subsequent monitoring of HMGB-1 levels, on the third and seventh day after admission, is encouraged for better evaluation of HMGB-1 as a prognostic marker of mortality in sepsis.
Background
: Activation of the receptor for advanced glycation end products (RAGE) and its ligand High Mobility Group Box Protein 1 (HMGB1), a nuclear protein with proinflammatory properties, has been implicated in several inflammatory disorders.
Objective
: To analyse the influence of RAGE and HMGB1 signalling in patients with primary sclerosing cholangitis (PSC).
Methods
: Levels of HMGB1 and bile acid in serum and bile samples of 69 PSC patients and 32 controls were measured. Additionally, 640 patients with PSC and other liver diseases were analysed for the gain-of-function RAGE G82S SNP by PCR. Laboratory and clinical parameters were retrieved by chart review.
Results
: ELISA analysis showed significantly higher biliary HMGB1 concentrations in PSC patients (n=69, median 124,1 ng/ml) than in the control group (n=32, median 6,85 ng/ml, p<0,001). Median serum HMGB1 (n=22, median 2,4 ng/ml) was significantly lower than median biliary HMGB1 of the concomitant bile samples (n=22, median 151 ng/ml, p =0,001). There was no correlation of biliary HMGB1 levels with laboratory parameters or clinical end points. Analysis of the gain-of-function G82SSNP RAGE SNP in PSC patients showed 8 patients with heterozygote mutant alleles (8/324, 2,5%). Patients carrying the mutation developed more often dominant strictures of the large bile ducts (100.0% vs. 61.3%; p=0.04) and had reduced transplantation-free survival in the mutant allele group (p<0.001).
Conclusions
: Biliary HMGB1 levels are elevated in PSC patients compared to controls and a gain-of-function SNP in RAGE is associated with development of dominant strictures and reduced survival in PSC patients.
High mobility group box (HMGB)1 action contributes to late phases of sepsis, but the effects of increased endogenous plasma HMGB1 levels on brain cells during inflammation are unclear. Here, we aimed to further investigate the role of HMGB1 in the brain during septic-like lipopolysaccharide-induced inflammation in rats (LPS, 10 mg/kg, i.p.). HMGB-1 mRNA expression and release were measured in the periphery/brain by RT-PCR, immunohistochemistry and ELISA. In vitro experiments with disulfide-HMGB1 in primary neuro-glial cell cultures of the area postrema (AP), a circumventricular organ with a leaky blood–brain barrier and direct access to circulating mediators like HMGB1 and LPS, were performed to determine the direct influence of HMGB1 on this pivotal brain structure for immune-to-brain communication. Indeed, HMGB1 plasma levels stayed elevated after LPS injection. Immunohistochemistry of brains and AP cultures confirmed LPS-stimulated cytoplasmatic translocation of HMGB1 indicative of local HMGB1 release. Moreover, disulfide-HMGB1 stimulation induced nuclear factor (NF)-κB activation and a significant release of interleukin-6, but not tumor necrosis factor α, into AP culture supernatants. However, only a few AP cells directly responded to HMGB1 with increased intracellular calcium concentration. Interestingly, priming with LPS induced a seven-fold higher percentage of responsive cells to HMGB1. We conclude that, as a humoral and local mediator, HMGB1 enhances brain inflammatory responses, after LPS priming, linked to sustained sepsis symptoms.
This paper presents the form and validation results of APACHE II, a severity of disease classification system. APACHE II uses a point score based upon initial values of 12 routine physiologic measurements, age, and previous health status to provide a general measure of severity of disease. An increasing score (range 0 to 71) was closely correlated with the subsequent risk of hospital death for 5815 intensive care admissions from 13 hospitals. This relationship was also found for many common diseases.When APACHE II scores are combined with an accurate description of disease, they can prognostically stratify acutely ill patients and assist investigators comparing the success of new or differing forms of therapy. This scoring index can be used to evaluate the use of hospital resources and compare the efficacy of intensive care in different hospitals or over time.
Endotoxin, a constituent of Gram-negative bacteria, stimulates macrophages to release large quantities of tumor necrosis factor
(TNF) and interleukin-1 (IL-1), which can precipitate tissue injury and lethal shock (endotoxemia). Antagonists of TNF and
IL-1 have shown limited efficacy in clinical trials, possibly because these cytokines are early mediators in pathogenesis.
Here a potential late mediator of lethality is identified and characterized in a mouse model. High mobility group–1 (HMG-1)
protein was found to be released by cultured macrophages more than 8 hours after stimulation with endotoxin, TNF, or IL-1.
Mice showed increased serum levels of HMG-1 from 8 to 32 hours after endotoxin exposure. Delayed administration of antibodies
to HMG-1 attenuated endotoxin lethality in mice, and administration of HMG-1 itself was lethal. Septic patients who succumbed
to infection had increased serum HMG-1 levels, suggesting that this protein warrants investigation as a therapeutic target.
Hyperglycemia and insulin resistance are common in critically ill patients, even if they have not previously had diabetes. Whether the normalization of blood glucose levels with insulin therapy improves the prognosis for such patients is not known.
We performed a prospective, randomized, controlled study involving adults admitted to our surgical intensive care unit who were receiving mechanical ventilation. On admission, patients were randomly assigned to receive intensive insulin therapy (maintenance of blood glucose at a level between 80 and 110 mg per deciliter [4.4 and 6.1 mmol per liter]) or conventional treatment (infusion of insulin only if the blood glucose level exceeded 215 mg per deciliter [11.9 mmol per liter] and maintenance of glucose at a level between 180 and 200 mg per deciliter [10.0 and 11.1 mmol per liter]).
At 12 months, with a total of 1548 patients enrolled, intensive insulin therapy reduced mortality during intensive care from 8.0 percent with conventional treatment to 4.6 percent (P<0.04, with adjustment for sequential analyses). The benefit of intensive insulin therapy was attributable to its effect on mortality among patients who remained in the intensive care unit for more than five days (20.2 percent with conventional treatment, as compared with 10.6 percent with intensive insulin therapy, P=0.005). The greatest reduction in mortality involved deaths due to multiple-organ failure with a proven septic focus. Intensive insulin therapy also reduced overall in-hospital mortality by 34 percent, bloodstream infections by 46 percent, acute renal failure requiring dialysis or hemofiltration by 41 percent, the median number of red-cell transfusions by 50 percent, and critical-illness polyneuropathy by 44 percent, and patients receiving intensive therapy were less likely to require prolonged mechanical ventilation and intensive care.
Intensive insulin therapy to maintain blood glucose at or below 110 mg per deciliter reduces morbidity and mortality among critically ill patients in the surgical intensive care unit.
A cDNA library constructed from mRNA of rat brain was used to clone the cDNA that encodes the 30-kDa heparin-binding protein (amphoterin) that is developmentally regulated in brain and enhances neurite outgrowth in cerebral neurons. cDNA and peptide sequencing identified a dipolar sequence that has been previously found in studies of high mobility group 1 protein: the 184-amino acid cationic region is followed by a cluster of 30 anionic residues. The mRNA encoding amphoterin is also developmentally regulated; it is strongly reduced in quantity after the rapid perinatal growth phase of the rat brain. Anti-synthetic peptide antibodies raised according to the sequence of amphoterin were shown to bind specifically to the protein isolated from brain, and were used to detect amphoterin in subcellular fractions and in immunostaining of cells. Amphoterin was found in the cytoplasm of the cell soma, in the cell processes, and the substrate-attached material. In cells that are at an active stage of spreading and extending their cytoplasmic processes amphoterin was especially associated with plasma membrane filopodia. The distinct localization to the filopodia of the advancing plasma membrane suggests that endogenous amphoterin has a role in the extension of neurite-type cytoplasmic processes in developing cells. This inference is further supported by the finding that both anti-amphoterin and the anti-synthetic peptide antibodies in the culture media strongly inhibit the outgrowth of cytoplasmic processes.
A membrane-bound adhesive protein that promotes neurite outgrowth in brain neurons has been isolated from rat brain (Rauvala, H., and R. Pihlaskari. 1987. J. Biol. Chem. 262:16625-16635). The protein is an immunochemically distinct molecule with a subunit size of approximately 30 kD (p30). p30 is an abundant protein in perinatal rat brain, but its content decreases rapidly after birth. In the present study the amino-terminal sequence of p30 was determined by automated Edman degradations. A single amino-terminal sequence was found, which is not present in previously studied adhesive molecules. This unique sequence has a cluster of five positive charges within the first 11 amino acid residues: Gly-Lys-Gly-Asp-Pro-Lys-Lys-Pro-Arg-Gly-Lys. Antisynthetic peptide antibodies that recognize this sequence were produced in a rabbit, purified with a peptide affinity column, and shown to bind specifically to p30. The antipeptide antibodies were used, together with anti-p30 antibodies, to study the localization of p30 in brain cells and in neuroblastoma cells as follows. (a) Immunofluorescence and immunoelectron microscopy indicated that p30 is a component of neurons in mixed cultures of brain cells. The neurons and the neuroblastoma cells expressed p30 at their surface in the cell bodies and the neurites. In the neurites p30 was found especially in the adhesive distal tips of the processes. In addition the protein was detected in ribosomal particles and in intracellular membranes in a proportion of cells. (b) The antibodies immobilized on microtiter wells enhanced adhesion and neurite growth indicating that p30 is surface exposed in adhering neural cells. (c) Immunoblotting showed that p30 is extracted from suspended cells by heparin suggesting that a heparin-like structure is required for the binding of p30 to the neuronal cell surface. A model summarizing the suggested interactions of p30 in cell adhesion and neurite growth is presented.
Fractionation of octyl glucoside-solubilized proteins from young rat brain was monitored using rat brain neurons, which were cultured in microwells coated with various protein fractions to be studied. An adhesive protein that promotes neurite outgrowth in rat brain neurons was isolated by chromatography on heparin-Sepharose followed by Affi-Gel blue. The apparent molecular mass of the protein in sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions was about 30 kilodaltons (p30). Under nonreducing conditions a closely spaced doublet band was observed corresponding to 27-28-kilodalton size. Gel filtration in the presence of 4 M urea indicated the molecular size of 58 kilodaltons suggesting a dimeric structure. Western blotting experiments using affinity-purified rabbit antibodies detected p30 as an immunochemically distinct protein in brain and in N18 neuroblastoma cells. The p30 protein was also detected in the N18 cells by lactoperoxidase-catalyzed cell surface iodination. Western blotting of heparin-binding proteins solubilized from brains of rats of various age groups indicated that p30 is clearly more abundant in perinatal brain as compared to adult tissue. The neuron-binding and neurite outgrowth-promoting properties of p30 as well as the developmental regulation of its content in brain tissue suggest a role in neuronal growth.
This paper presents the form and validation results of APACHE II, a severity of disease classification system. APACHE II uses a point score based upon initial values of 12 routine physiologic measurements, age, and previous health status to provide a general measure of severity of disease. An increasing score (range 0 to 71) was closely correlated with the subsequent risk of hospital death for 5815 intensive care admissions from 13 hospitals. This relationship was also found for many common diseases. When APACHE II scores are combined with an accurate description of disease, they can prognostically stratify acutely ill patients and assist investigators comparing the success of new or differing forms of therapy. This scoring index can be used to evaluate the use of hospital resources and compare the efficacy of intensive care in different hospitals or over time.
The case fatality rate in bacteremic pneumococcal pneumonia (Pnb) has been reported to be lower in Sweden than in the United States. We retrospectively compared 231 adult Pnb patients in Stockholm (STO), Sweden, with 107 patients infected with the same serotypes or groups in Huntington, WVa (HWV). The total case fatality rate was 11/231 (5 percent) in STO versus 28/107 (26 percent) in HWV (p < 0.001), being significantly lower in STO for all age groups. Patients from HWV more often had preexisting chronic diseases, while alcoholism was more prevalent in STO. The case fatality rate was similar among alcoholics in STO and HWV, while it was much higher in nonalcoholic patients with chronic diseases in HWV (22/73;30 percent) than in STO (2/88;2 percent) (p < 0.001). No bias was found that could account for more than a small part of the higher case fatality rate in HWV. Thus, underlying chronic diseases in HWV accounted for some of the increased risk of death in this patient group. However, the major part of the difference in death rates between HWV and STO remains unexplained.
A recombinant, soluble fusion protein that is a dimer of an extracellular portion of the human tumor necrosis factor (TNF) receptor and the Fc portion of IgG1 (TNFR:Fc) binds and neutralizes TNF-alpha and prevents death in animal models of bacteremia and endotoxemia.
To evaluate the safety and efficacy of TNFR:Fc in the treatment of septic shock, we conducted a randomized, double-blind, placebo-controlled, multicenter trial. A total of 141 patients were randomly assigned to receive either placebo or a single intravenous infusion of one of three doses of TNFR:Fc (0.15, 0.45, or 1.5 mg per kilogram of body weight). The primary end point was mortality from all causes at 28 days.
There were 10 deaths among the 33 patients in the placebo group (30 percent mortality), 9 deaths among the 30 patients receiving the low dose of TNFR:Fc (30 percent mortality), 14 deaths among the 29 receiving the middle dose (48 percent mortality), and 26 deaths among the 49 receiving the high dose (53 percent mortality) (P = 0.02 for the dose-response relation). Baseline differences in the severity of illness did not account for the increased mortality in the groups receiving the higher doses of TNFR:Fc.
In patients with septic shock, treatment with the TNFR:Fc fusion protein does not reduce mortality, and higher doses appear to be associated with increased mortality.
Acute inflammatory lung injury is often a delayed complication of critical illness and is associated with increased mortality. High mobility group-1 (HMG-1) protein, in addition to its role as a transcriptional regulatory factor, has recently been identified as a late mediator of endotoxin lethality. In the present studies, HMG-1 given intratracheally produced acute inflammatory injury to the lungs, with neutrophil accumulation, the development of lung edema, and increased pulmonary production of IL-1beta, TNF-alpha, and macrophage-inflammatory protein-2. In endotoxin-induced acute lung inflammation, administration of anti-HMG-1 Abs either before or after endotoxin exposure decreased the migration of neutrophils to the lungs as well as lung edema. These protective effects of anti-HMG-1 were specific, because pulmonary levels of IL-1beta, TNF-alpha, or macrophage-inflammatory protein-2 were not decreased after therapy with anti-HMG-1. Together, these findings indicate that HMG-1 is a distal mediator of acute inflammatory lung injury.
Drotrecogin alfa (activated), or recombinant human activated protein C, has antithrombotic, antiinflammatory, and profibrinolytic properties. In a previous study, drotrecogin alfa activated produced dose-dependent reductions in the levels of markers of coagulation and inflammation in patients with severe sepsis. In this phase 3 trial, we assessed whether treatment with drotrecogin alfa activated reduced the rate of death from any cause among patients with severe sepsis.
We conducted a randomized, double-blind, placebo-controlled, multicenter trial. Patients with systemic inflammation and organ failure due to acute infection were enrolled and assigned to receive an intravenous infusion of either placebo or drotrecogin alfa activated (24 microg per kilogram of body weight per hour) for a total duration of 96 hours. The prospectively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion. Patients were monitored for adverse events; changes in vital signs, laboratory variables, and the results of microbiologic cultures; and the development of neutralizing antibodies against activated protein C.
A total of 1690 randomized patients were treated (840 in the placebo group and 850 in the drotrecogin alfa activated group). The mortality rate was 30.8 percent in the placebo group and 24.7 percent in the drotrecogin alfa activated group. On the basis of the prospectively defined primary analysis, treatment with drotrecogin alfa activated was associated with a reduction in the relative risk of death of 19.4 percent (95 percent confidence interval, 6.6 to 30.5) and an absolute reduction in the risk of death of 6.1 percent (P=0.005). The incidence of serious bleeding was higher in the drotrecogin alfa activated group than in the placebo group (3.5 percent vs. 2.0 percent, P=0.06).
Treatment with drotrecogin alfa activated significantly reduces mortality in patients with severe sepsis and may be associated with an increased risk of bleeding.
Goal-directed therapy has been used for severe sepsis and septic shock in the intensive care unit. This approach involves adjustments of cardiac preload, afterload, and contractility to balance oxygen delivery with oxygen demand. The purpose of this study was to evaluate the efficacy of early goal-directed therapy before admission to the intensive care unit.
We randomly assigned patients who arrived at an urban emergency department with severe sepsis or septic shock to receive either six hours of early goal-directed therapy or standard therapy (as a control) before admission to the intensive care unit. Clinicians who subsequently assumed the care of the patients were blinded to the treatment assignment. In-hospital mortality (the primary efficacy outcome), end points with respect to resuscitation, and Acute Physiology and Chronic Health Evaluation (APACHE II) scores were obtained serially for 72 hours and compared between the study groups.
Of the 263 enrolled patients, 130 were randomly assigned to early goal-directed therapy and 133 to standard therapy; there were no significant differences between the groups with respect to base-line characteristics. In-hospital mortality was 30.5 percent in the group assigned to early goal-directed therapy, as compared with 46.5 percent in the group assigned to standard therapy (P = 0.009). During the interval from 7 to 72 hours, the patients assigned to early goal-directed therapy had a significantly higher mean (+/-SD) central venous oxygen saturation (70.4+/-10.7 percent vs. 65.3+/-11.4 percent), a lower lactate concentration (3.0+/-4.4 vs. 3.9+/-4.4 mmol per liter), a lower base deficit (2.0+/-6.6 vs. 5.1+/-6.7 mmol per liter), and a higher pH (7.40+/-0.12 vs. 7.36+/-0.12) than the patients assigned to standard therapy (P < or = 0.02 for all comparisons). During the same period, mean APACHE II scores were significantly lower, indicating less severe organ dysfunction, in the patients assigned to early goal-directed therapy than in those assigned to standard therapy (13.0+/-6.3 vs. 15.9+/-6.4, P < 0.001).
Early goal-directed therapy provides significant benefits with respect to outcome in patients with severe sepsis and septic shock.
To examine the incidence of infections and to describe them and their outcome in intensive care unit (ICU) patients.
International prospective cohort study in which all patients admitted to the 28 participating units in eight countries between May 1997 and May 1998 were followed until hospital discharge.
A total of 14,364 patients were admitted to the ICUs, 6011 of whom stayed less than 24 h and 8353 more than 24 h.
Overall 3034 infectious episodes were recorded at ICU admission (crude incidence: 21.1%). In ICU patients hospitalised longer than 24 h there were 1581 infectious episodes (crude incidence: 18.9%) including 713 (45%) in patients already infected at ICU admission. These rates varied between ICUs. Respiratory, digestive, urinary tracts, and primary bloodstream infections represented about 80% of all sites. Hospital-acquired and ICU-acquired infections were documented more frequently microbiologically than community-acquired infections (71% and 86%, respectively vs. 55%). About 28% of infections were associated with sepsis, 24% with severe sepsis and 30% with septic shock, and 18% were not classified. Crude hospital mortality rates ranged from 16.9% in non-infected patients to 53.6% in patients with hospital-acquired infections at the time of ICU admission and acquiring infection during the ICU stay.
The crude incidence of ICU infections remains high, although the rate varies between ICUs and patient subsets, illustrating the added burden of nosocomial infections in the use of ICU resources.
Septic shock may be associated with relative adrenal insufficiency. Thus, a replacement therapy of low doses of corticosteroids has been proposed to treat septic shock.
To assess whether low doses of corticosteroids improve 28-day survival in patients with septic shock and relative adrenal insufficiency.
Placebo-controlled, randomized, double-blind, parallel-group trial performed in 19 intensive care units in France from October 9, 1995, to February 23, 1999.
Three hundred adult patients who fulfilled usual criteria for septic shock were enrolled after undergoing a short corticotropin test.
Patients were randomly assigned to receive either hydrocortisone (50-mg intravenous bolus every 6 hours) and fludrocortisone (50- micro g tablet once daily) (n = 151) or matching placebos (n = 149) for 7 days.
Twenty-eight-day survival distribution in patients with relative adrenal insufficiency (nonresponders to the corticotropin test).
One patient from the corticosteroid group was excluded from analyses because of consent withdrawal. There were 229 nonresponders to the corticotropin test (placebo, 115; corticosteroids, 114) and 70 responders to the corticotropin test (placebo, 34; corticosteroids, 36). In nonresponders, there were 73 deaths (63%) in the placebo group and 60 deaths (53%) in the corticosteroid group (hazard ratio, 0.67; 95% confidence interval, 0.47-0.95; P =.02). Vasopressor therapy was withdrawn within 28 days in 46 patients (40%) in the placebo group and in 65 patients (57%) in the corticosteroid group (hazard ratio, 1.91; 95% confidence interval, 1.29-2.84; P =.001). There was no significant difference between groups in responders. Adverse events rates were similar in the 2 groups.
In our trial, a 7-day treatment with low doses of hydrocortisone and fludrocortisone significantly reduced the risk of death in patients with septic shock and relative adrenal insufficiency without increasing adverse events.
The efficacy and safety of high-dose intravenous polyspecific immunoglobulin G (IVIG) as adjunctive therapy in streptococcal
toxic shock syndrome (STSS) were evaluated in a multicenter, randomized, double-blind, placebo-controlled trial. The trial
was prematurely terminated because of slow patient recruitment, and results were obtained from 21 enrolled patients (10 IVIG
recipients and 11 placebo recipients). The primary end point was mortality at 28 days, and a 3.6-fold higher mortality rate
was found in the placebo group. A significant decrease in the sepsis-related organ failure assessment score at days 2 (P = .02) and 3 (P = .04) was noted in the IVIG group. Furthermore, a significant increase in plasma neutralizing activity against superantigens
expressed by autologous isolates was noted in the IVIG group after treatment (P = .03). Although statistical significance was not reached in the primary end point, the trial provides further support for
IVIG as an efficacious adjunctive therapy in STSS.
Despite significant advances in intensive care therapy and antibiotics, severe sepsis accounts for 9% of all deaths in the United States annually. The pathological sequelae of sepsis are characterized by a systemic inflammatory response, but experimental therapeutics that target specific early inflammatory mediators [tumor necrosis factor (TNF) and IL-1beta] have not proven efficacious in the clinic. We recently identified high mobility group box 1 (HMGB1) as a late mediator of endotoxin-induced lethality that exhibits significantly delayed kinetics relative to TNF and IL-1beta. Here, we report that serum HMGB1 levels are increased significantly in a standardized model of murine sepsis, beginning 18 h after surgical induction of peritonitis. Specific inhibition of HMGB1 activity [with either anti-HMGB1 antibody (600 microg per mouse) or the DNA-binding A box (600 microg per mouse)] beginning as late as 24 h after surgical induction of peritonitis significantly increased survival (nonimmune IgG-treated controls = 28% vs. anti-HMGB1 antibody group = 72%, P < 0.03; GST control protein = 28% vs. A box = 68%, P < 0.03). Animals treated with either HMGB1 antagonist were protected against the development of organ injury, as evidenced by improved levels of serum creatinine and blood urea nitrogen. These observations demonstrate that specific inhibition of endogenous HMGB1 therapeutically reverses lethality of established sepsis indicating that HMGB1 inhibitors can be administered in a clinically relevant time frame.
To evaluate the efficacy and safety of anti-tumor necrosis factor alpha monoclonal antibody (TNF-alpha MAb) in the treatment of patients with sepsis syndrome. Randomized, prospective, multicenter, double-blind, placebo-controlled clinical trial. A total of 31 hospitals in the United States and Canada. There were 994 patients with sepsis syndrome enrolled in this clinical trial, and 971 patients were infused with the study drug. Patients were prospectively stratified into shock or nonshock groups and then randomized to receive a single infusion of 15 mg/kg of TNF-alpha MAb, 7.5 mg/kg of TNF-alpha MAb, or placebo. Patients received standard aggressive medical and surgical care during the 28-day postinfusion period. Twenty-eight-day all-cause mortality. The distribution of variables describing demographics, organ system dysfunction or failure, preinfusion Acute Physiology and Chronic Health Evaluation II score, number of organs failing at baseline, initial sites of infection, infecting microorganisms, antimicrobials used, and initial invasive procedures was similar among patients in the TNF-alpha MAb and placebo treatment arms. Among all infused patients, there was no difference in all-cause mortality in patients who received placebo as compared with those who received TNF-alpha MAb. In septic patients with shock (n = 478), there was a trend toward a reduction in all-cause mortality, which was most evident 3 days after infusion: 25 of 162 patients treated with 15 mg/kg of TNF-alpha MAb died, 22 of 156 patients treated with 7.5 mg/kg of TNF-alpha MAb died, and 44 of 160 patients in the placebo group died (15 mg/kg: 44% reduction vs placebo, P = .01; 7.5 mg/kg: 48.7% reduction vs placebo, P = .004). At day 28, the reduction in mortality for shock patients was not significant for either dose of TNF-alpha MAb relative to placebo (15 mg/kg, 61 deaths among 162 patients [37.7% mortality]; 7.5 mg/kg, 59 deaths among 156 patients [37.8% mortality]; placebo, 73 deaths among 160 patients [45.6% mortality]; P = .20 for 7.5 mg/kg and P = .15 for 15 mg/kg). Serious adverse events were reported in 4.6% of all infused patients. No immediate hypersensitivity allergic reactions due to TNF-alpha MAb were reported. Serum sickness-like reactions were seen in 2.5% of patients receiving TNF-alpha MAb. There was no decrease in mortality between placebo and TNF-alpha MAb in all infused patients. In septic shock patients who received TNF-alpha MAb, a significant reduction in mortality was present 3 days after infusion. Although a trend toward reduced mortality continued at 28 days following treatment with TNF-alpha MAb, the difference in mortality among shock patients treated with placebo or TNF-alpha MAb was not significant.
A membrane-bound adhesive protein that promotes neurite outgrowth in brain neurons has been isolated from rat brain (Rauvala, H., and R. Pihlaskari. 1987. J. Biol. Chem. 262:16625-16635). The protein is an immunochemically distinct molecule with a subunit size of approximately 30 kD (p30). p30 is an abundant protein in perinatal rat brain, but its content decreases rapidly after birth. In the present study the amino-terminal sequence of p30 was determined by automated Edman degradations. A single amino-terminal sequence was found, which is not present in previously studied adhesive molecules. This unique sequence has a cluster of five positive charges within the first 11 amino acid residues: Gly-Lys-Gly-Asp-Pro-Lys-Lys-Pro-Arg-Gly-Lys. Antisynthetic peptide antibodies that recognize this sequence were produced in a rabbit, purified with a peptide affinity column, and shown to bind specifically to p30. The antipeptide antibodies were used, together with anti-p30 antibodies, to study the localization of p30 in brain cells and in neuroblastoma cells as follows. (a) Immunofluorescence and immunoelectron microscopy indicated that p30 is a component of neurons in mixed cultures of brain cells. The neurons and the neuroblastoma cells expressed p30 at their surface in the cell bodies and the neurites. In the neurites p30 was found especially in the adhesive distal tips of the processes. In addition the protein was detected in ribosomal particles and in intracellular membranes in a proportion of cells. (b) The antibodies immobilized on microtiter wells enhanced adhesion and neurite growth indicating that p30 is surface exposed in adhering neural cells. (c) Immunoblotting showed that p30 is extracted from suspended cells by heparin suggesting that a heparin-like structure is required for the binding of p30 to the neuronal cell surface. A model summarizing the suggested interactions of p30 in cell adhesion and neurite growth is presented.
An American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference was held in Northbrook in August 1991 with the goal of agreeing on a set of definitions that could be applied to patients with sepsis and its sequelae. New definitions were offered for some terms, while others were discarded. Broad definitions of sepsis and the systemic inflammatory response syndrome were proposed, along with detailed physiologic parameters by which a patient may be categorized. Definitions for severe sepsis, septic shock, hypotension, and multiple organ dysfunction syndrome were also offered. The use of severity scoring methods when dealing with septic patients was recommended as an adjunctive tool to assess mortality. Appropriate methods and applications for the use and testing of new therapies were recommended. The use of these terms and techniques should assist clinicians and researchers who deal with sepsis and its sequelae.
Objective.
—To evaluate the efficacy and safety of anti—tumor necrosis factor α monoclonal antibody (TNF-α MAb) in the treatment of patients with sepsis syndrome.Design.
—Randomized, prospective, multicenter, double-blind, placebo-controlled clinical trial.Setting.
—A total of 31 hospitals in the United States and Canada.Patients.
—There were 994 patients with sepsis syndrome enrolled in this clinical trial, and 971 patients were infused with the study drug.Intervention.
—Patients were prospectively stratified into shock or nonshock groups and then randomized to receive a single infusion of 15 mg/kg of TNF-α MAb, 7.5 mg/kg of TNF-α MAb, or placebo. Patients received standard aggressive medical and surgical care during the 28-day postinfusion period.Outcome Measure.
—Twenty-eight-day all-cause mortality.Results.
—The distribution of variables describing demographics, organ system dysfunction or failure, preinfusion Acute Physiology and Chronic Health Evaluation II score, number of organs failing at baseline, initial sites of infection, infecting microorganisms, antimicrobials used, and initial invasive procedures was similar among patients in the TNF-α MAb and placebo treatment arms. Among all infused patients, there was no difference in all-cause mortality in patients who received placebo as compared with those who received TNF-α MAb. In septic patients with shock (n=478), there was a trend toward a reduction in all-cause mortality, which was most evident 3 days after infusion: 25 of 162 patients treated with 15 mg/kg of TNF-α MAb died, 22 of 156 patients treated with 7.5 mg/kg of TNF-α MAb died, and 44 of 160 patients in the placebo group died (15 mg/kg: 44% reduction vs placebo, P=.01; 7.5 mg/kg: 48.7% reduction vs placebo, P=.004). At day 28, the reduction in mortality for shock patients was not significant for either dose of TNF-α MAb relative to placebo (15 mg/kg, 61 deaths among 162 patients [37.7% mortality]; 7.5 mg/kg, 59 deaths among 156 patients [37.8% mortality]; placebo, 73 deaths among 160 patients [45.6% mortality]; P=.20 for 7.5 mg/kg and P=.15 for 15 mg/kg). Serious adverse events were reported in 4.6% of all infused patients. No immediate hypersensitivity allergic reactions due to TNF-α MAb were reported. Serum sickness—like reactions were seen in 2.5% of patients receiving TNF-α MAb.Conclusions.
—There was no decrease in mortality between placebo and TNF-α MAb in all infused patients. In septic shock patients who received TNF-α MAb, a significant reduction in mortality was present 3 days after infusion. Although a trend toward reduced mortality continued at 28 days following treatment with TNF-α MAb, the difference in mortality among shock patients treated with placebo or TNF-α MAb was not significant.(JAMA. 1995;273:934-941)
Background
In animal studies, gender differences were related to hormonal and immunologic changes that were associated with an increased susceptibility to sepsis in males.
Objective
In a prospective study, gender differences in patients with surgical sepsis were evaluated in terms of survival, sex hormones, and proinflammatory as well as anti-inflammatory mediators.
Setting
Surgical intensive care unit of a university hospital.
Patients
Fifty-two patients (19 women and 33 men) with surgical sepsis.
Measurements and Main Results
In a prospective study, tumor necrosis factor α and interleukin 6 bioactivity and plasma levels of interleukin 10 (using enzyme-linked immunosorbent assay), total testosterone, and 17-β estradiol (using radioimmunoassay) were determined on days 1, 3, 5, 7, 10, and 14 after diagnosis of sepsis. There were no differences in characteristics of patients in age (mean age, 55.4 years for women and 53.1 years for men) or cause and severity of sepsis (Acute Physiology and Chronic Health Evaluation II score, 17.3 for women and 18.5 for men; multiple organ dysfunction score, 9.9 vs 10.8, respectively). Although no difference could be found in the multiple organ dysfunction score from day 1 to day 28, the prognosis of sepsis was significantly different in women compared with men. Hospital mortality rate was 70% (23 of 33 patients) in male and 26% (5 of 19) in female patients (P<.008, log-rank test). Bioactivity of tumor necrosis factor continuously increased in men after diagnosis of sepsis, with significantly elevated levels on day 10 (P<.05, Mann-Whitney U test with Bonferroni correction), whereas no difference was found for interleukin 6 bioactivity. Women displayed enhanced interleukin 10 levels compared with men from day 1 to day 10 that reached a significant difference on days 3 and 5 (P<.05). Total testosterone levels were below the normal range for men, and estradiol levels were initially increased in both men and postmenopausal women, with higher levels for women.
Conclusions
In this prospective study, gender differences were confirmed in human sepsis, with a significantly better prognosis for women, which may be related to increased levels of anti-inflammatory mediators. The hypothetical different ratio of proinflammatory and anti-inflammatory mediators may be important for further therapeutic interventions in sepsis.
Objectives: To evaluate the safety, pharmacokinetics, and efficacy of human recombinant interleukin-1 receptor antagonist (IL-lra) in the treatment of patients with sepsis syndrome. Design: Prospective, open-label, placebo-controlled, phase II, multicenter clinical trial using three different doses of human recombinant ILlra. Setting: Twelve academic medical center intensive care units in the United States. Patients: Ninety-nine patients with sepsis syndrome or septic shock who received standard supportive care and antimicrobial therapy, in addition to infusion with escalating doses of ILlra or placebo. Interventions: Patients received an intravenous loading dose of either human recombinant IL-lra (100 mg) or placebo, followed by a 72-hr intravenous infusion of either one of three doses of BL-lra (17, 67, or 133 mg/hr) or placebo. All patients were evaluated for 28-day, all-cause mortality. Measurements and Main Results: A dosedependent, 28-day survival benefit was associated with IL-lra treatment (p = .015), as indicated by the following mortality rates: 11 (44%) deaths among 25 placebo patients; eight (32%) deaths among 25 patients receiving IL-lra 17 mg/hr; six (25%) deaths among 24 patients receiving IL-lra 67 mg/hr; and four (16%) deaths among 25 patients receiving IL-lra 133 mg/hr. A dose-related survival benefit was observed with infusion of IL-lra in patients with septic shock at study entry (n = 65; p = .002) and in patients with Gram-negative infection (n = 45; p = .04). Patients with an increased circulating interleukin-6 (IL-6) concentration of >100 pg/ mL at study entry demonstrated a dose-related survival benefit with IL-lra treatment (p = .009). In patients with an increased IL-6 concentration at study entry, the magnitude of the decrease in IL-6 concentration 24 hrs after the initiation of therapy was correlated with increasing the IL-lra treatment dose (p = .052). A significant dose-related reduction in the Acute Physiology and Chronic Health Evaluation (APACHE II) score was achieved by the end of infusion (p = .038). A renal elimination mechanism for IL-lra was suggested by the positive correlation between IL-lra plasma clearance and estimated creatinine clearance (p = .001; r2 = .51). Human recombinant IL-lra was well tolerated. Conclusions: This initial evaluation suggests that human recombinant IL-lra is safe and may provide a dose-related survival advantage to patients with sepsis syndrome. A larger, definitive clinical trial is needed to confirm these findings. (Crit Care Med 1994; 22:12-21)
Objective: To determine the incidence, cost, and outcome of severe sepsis in the United States.
Design: Observational cohort study.
Setting: All nonfederal hospitals (n = 847) in seven U.S. states.
Patients: All patients (n = 192,980) meeting criteria for severe sepsis based on the International Classification of Diseases, Ninth Revision, Clinical Modification.
Interventions: None.
Measurements and Main Results : We linked all 1995 state hospital discharge records (n = 6,621,559) from seven large states with population and hospital data from the U.S. Census, the Centers for Disease Control, the Health Care Financing Administration, and the American Hospital Association. We defined severe sepsis as documented infection and acute organ dysfunction using criteria based on the International Classification of Diseases, Ninth Revision, Clinical Modification. We validated these criteria against prospective clinical and physiologic criteria in a subset of five hospitals. We generated national age- and gender-adjusted estimates of incidence, cost, and outcome. We identified 192,980 cases, yielding national estimates of 751,000 cases (3.0 cases per 1,000 population and 2.26 cases per 100 hospital discharges), of whom 383,000 (51.1%) received intensive care and an additional 130,000 (17.3%) were ventilated in an intermediate care unit or cared for in a coronary care unit. Incidence increased >100-fold with age (0.2/1,000 in children to 26.2/1,000 in those >85 yrs old). Mortality was 28.6%, or 215,000 deaths nationally, and also increased with age, from 10% in children to 38.4% in those >85 yrs old. Women had lower age-specific incidence and mortality, but the difference in mortality was explained by differences in underlying disease and the site of infection. The average costs per case were $22,100, with annual total costs of $16.7 billion nationally. Costs were higher in infants, nonsurvivors, intensive care unit patients, surgical patients, and patients with more organ failure. The incidence was projected to increase by 1.5% per annum.
Conclusions: Severe sepsis is a common, expensive, and frequently fatal condition, with as many deaths annually as those from acute myocardial infarction. It is especially common in the elderly and is likely to increase substantially as the U.S. population ages.
The abstract for this document is available on CSA Illumina.To view the Abstract, click the Abstract button above the document title.
An American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference was held in Northbrook in August 1991 with the goal of agreeing on a set of definitions that could be applied to patients with sepsis and its sequelae. New definitions were offered for some terms, while others were discarded. Broad definitions of sepsis and the systemic inflammatory response syndrome were proposed, along with detailed physiologic parameters by which a patient may be categorized. Definitions for severe sepsis, septic shock, hypotension, and multiple organ dysfunction syndrome were also offered. The use of severity scoring methods when dealing with septic patients was recommended as an adjunctive tool to assess mortality. Appropriate methods and applications for the use and testing of new therapies were recommended. The use of these terms and techniques should assist clinicians and researchers who deal with sepsis and its sequelae.
HA-1A is a human monoclonal IgM antibody that binds specifically to the lipid A domain of endotoxin and prevents death in laboratory animals with gram-negative bacteremia and endotoxemia.
To evaluate the efficacy and safety of HA-1A, we conducted a randomized, double-blind trial in patients with sepsis and a presumed diagnosis of gram-negative infection. The patients received either a single 100-mg intravenous dose of HA-1A (in 3.5 g of albumin) or placebo (3.5 g of albumin). Other interventions, including the administration of antibiotics and fluids, were not affected by the study protocol.
Of 543 patients with sepsis who were treated, 200 (37 percent) had gram-negative bacteremia as proved by blood culture. For the patients with gram-negative bacteremia followed to death or day 28, there were 45 deaths among the 92 recipients of placebo (49 percent) and 32 deaths among the 105 recipients of HA-1A (30 percent; P = 0.014). For the patients with gram-negative bacteremia and shock at entry, there were 27 deaths among the 47 recipients of placebo (57 percent) and 18 deaths among the 54 recipients of HA-1A (33 percent; P = 0.017). Analyses that stratified according to the severity of illness at entry showed improved survival with HA-1A treatment in both severely ill and less severely ill patients. Of the 196 patients with gram-negative bacteremia who were followed to hospital discharge or death, 45 of the 93 given placebo (48 percent) were discharged alive, as compared with 65 of the 103 treated with HA-1A (63 percent; P = 0.038). No benefit of treatment with HA-1A was demonstrated in the 343 patients with sepsis who did not prove to have gram-negative bacteremia. For all 543 patients with sepsis who were treated, the mortality rate was 43 percent among the recipients of placebo and 39 percent among those given HA-1A (P = 0.24). All patients tolerated HA-1A well, and no anti-HA-1A antibodies were detected.
HA-1A is safe and effective for the treatment of patients with sepsis and gram-negative bacteremia.
To evaluate the efficacy and safety of anti-tumor necrosis factor alpha monoclonal antibody (TNF-alpha MAb) in the treatment of patients with sepsis syndrome.
Randomized, prospective, multicenter, double-blind, placebo-controlled clinical trial.
A total of 31 hospitals in the United States and Canada.
There were 994 patients with sepsis syndrome enrolled in this clinical trial, and 971 patients were infused with the study drug.
Patients were prospectively stratified into shock or nonshock groups and then randomized to receive a single infusion of 15 mg/kg of TNF-alpha MAb, 7.5 mg/kg of TNF-alpha MAb, or placebo. Patients received standard aggressive medical and surgical care during the 28-day postinfusion period.
Twenty-eight-day all-cause mortality.
The distribution of variables describing demographics, organ system dysfunction or failure, preinfusion Acute Physiology and Chronic Health Evaluation II score, number of organs failing at baseline, initial sites of infection, infecting microorganisms, antimicrobials used, and initial invasive procedures was similar among patients in the TNF-alpha MAb and placebo treatment arms. Among all infused patients, there was no difference in all-cause mortality in patients who received placebo as compared with those who received TNF-alpha MAb. In septic patients with shock (n = 478), there was a trend toward a reduction in all-cause mortality, which was most evident 3 days after infusion: 25 of 162 patients treated with 15 mg/kg of TNF-alpha MAb died, 22 of 156 patients treated with 7.5 mg/kg of TNF-alpha MAb died, and 44 of 160 patients in the placebo group died (15 mg/kg: 44% reduction vs placebo, P = .01; 7.5 mg/kg: 48.7% reduction vs placebo, P = .004). At day 28, the reduction in mortality for shock patients was not significant for either dose of TNF-alpha MAb relative to placebo (15 mg/kg, 61 deaths among 162 patients [37.7% mortality]; 7.5 mg/kg, 59 deaths among 156 patients [37.8% mortality]; placebo, 73 deaths among 160 patients [45.6% mortality]; P = .20 for 7.5 mg/kg and P = .15 for 15 mg/kg). Serious adverse events were reported in 4.6% of all infused patients. No immediate hypersensitivity allergic reactions due to TNF-alpha MAb were reported. Serum sickness-like reactions were seen in 2.5% of patients receiving TNF-alpha MAb.
There was no decrease in mortality between placebo and TNF-alpha MAb in all infused patients. In septic shock patients who received TNF-alpha MAb, a significant reduction in mortality was present 3 days after infusion. Although a trend toward reduced mortality continued at 28 days following treatment with TNF-alpha MAb, the difference in mortality among shock patients treated with placebo or TNF-alpha MAb was not significant.
To evaluate the safety, pharmacokinetics, and efficacy of human recombinant interleukin-1 receptor antagonist (IL-1ra) in the treatment of patients with sepsis syndrome.
Prospective, open-label, placebo-controlled, phase II, multicenter clinical trial using three different doses of human recombinant IL-1ra.
Twelve academic medical center intensive care units in the United States.
Ninety-nine patients with sepsis syndrome or septic shock who received standard supportive care and antimicrobial therapy, in addition to infusion with escalating doses of IL-1ra or placebo.
Patients received an intravenous loading dose of either human recombinant IL-1ra (100 mg) or placebo, followed by a 72-hr intravenous infusion of either one of three doses of IL-1ra (17, 67, or 133 mg/hr) or placebo. All patients were evaluated for 28-day, all-cause mortality.
A dose-dependent, 28-day survival benefit was associated with IL-1ra treatment (p = .015), as indicated by the following mortality rates: 11 (44%) deaths among 25 placebo patients; eight (32%) deaths among 25 patients receiving IL-1ra 17 mg/hr; six (25%) deaths among 24 patients receiving IL-1ra 67 mg/hr; and four (16%) deaths among 25 patients receiving IL-1ra 133 mg/hr. A dose-related survival benefit was observed with infusion of IL-1ra in patients with septic shock at study entry (n = 65; p = .002) and in patients with Gram-negative infection (n = 45; p = .04). Patients with an increased circulating interleukin-6 (IL-6) concentration of > 100 pg/mL at study entry demonstrated a dose-related survival benefit with IL-1ra treatment (p = .009). In patients with an increased IL-6 concentration at study entry, the magnitude of the decrease in IL-6 concentration 24 hrs after the initiation of therapy was correlated with increasing the IL-1ra treatment dose (p = .052). A significant dose-related reduction in the Acute Physiology and Chronic Health Evaluation (APACHE II) score was achieved by the end of infusion (p = .038). A renal elimination mechanism for IL-1ra was suggested by the positive correlation between IL-1ra plasma clearance and estimated creatinine clearance (p = .001; r2 = .51). Human recombinant IL-1ra was well tolerated.
This initial evaluation suggests that human recombinant IL-1ra is safe and may provide a dose-related survival advantage to patients with sepsis syndrome. A larger, definitive clinical trial is needed to confirm these findings.
Amphoterin is a heparin-binding protein that is developmentally regulated in brain and functionally involved in neurite outgrowth. Unexpectedly, amphoterin has a high mobility group 1 (HMG1)-type sequence. In the present study we have expressed amphoterin cDNA in a baculovirus vector and produced antibodies against the recombinant protein and several synthetic peptides. It was found that the amphoterin cDNA encodes the 30-kDa form of the protein isolated from tissues, whereas the co-purifying 28- and 29-kDa proteins (p28 and p29) have closely related but distinct primary structures. Partial amino acid sequencing shows several local changes in the sequences of p28 and p29 compared with amphoterin, suggesting the occurrence of a multigene family that encodes at least three different HMG1-type sequences in the rat. Studies using the probes that discern amphoterin from the other HMG1-type proteins indicate a high level expression in various transformed cell lines. Immunostaining of cells with the amphoterin-specific antibodies indicates a cytoplasmic localization that becomes remarkably enriched at the leading edges in spreading and motile cells. An extracellular localization is suggested by immunostaining of nonpermeabilized cells and by a plasminogen-dependent degradation of amphoterin in the substratum-attached material of cells. Tissue-derived and recombinant amphoterins strongly enhance the rate of plasminogen activation and promote the generation of surface-bound plasmin both by tissue-type and urokinase-type plasminogen activators. The results suggest an extracellular function for amphoterin in the leading edge of various invasive cells.
In animal studies, gender differences were related to hormonal and immunologic changes that were associated with an increased susceptibility to sepsis in males.
In a prospective study, gender differences in patients with surgical sepsis were evaluated in terms of survival, sex hormones, and proinflammatory as well as anti-inflammatory mediators.
Surgical intensive care unit of a university hospital.
Fifty-two patients (19 women and 33 men) with surgical sepsis.
In a prospective study, tumor necrosis factor alpha and interleukin 6 bioactivity and plasma levels of interleukin 10 (using enzyme-linked immunosorbent assay), total testosterone, and 17-beta estradiol (using radioimmunoassay) were determined on days 1, 3, 5, 7, 10, and 14 after diagnosis of sepsis. There were no differences in characteristics of patients in age (mean age, 55.4 years for women and 53.1 years for men) or cause and severity of sepsis (Acute Physiology and Chronic Health Evaluation II score, 17.3 for women and 18.5 for men; multiple organ dysfunction score, 9.9 vs 10.8, respectively). Although no difference could be found in the multiple organ dysfunction score from day 1 to day 28, the prognosis of sepsis was significantly different in women compared with men. Hospital-mortality rate was 70% (23 of 33 patients) in male and 26% (5 of 19) in female patients (P<.008, log-rank test). Bioactivity of tumor necrosis factor continuously increased in men after diagnosis of sepsis, with significantly elevated levels on day 10 (P<.05, Mann-Whitney U test with Bonferroni correction), whereas no difference was found for interleukin 6 bioactivity. Women displayed enhanced interleukin 10 levels compared with men from day 1 to day 10 that reached a significant difference on days 3 and 5 (P<.05). Total testosterone levels were below the normal range for men, and estradiol levels were initially increased in both men and postmenopausal women, with higher levels for women.
In this prospective study, gender differences were confirmed in human sepsis, with a significantly better prognosis for women, which may be related to increased levels of anti-inflammatory mediators. The hypothetical different ratio of proinflammatory and anti-inflammatory mediators may be important for further therapeutic interventions in sepsis.
To determine whether a systematic review of the literature could identify changes in the mortality of septic shock over time.
A review of all relevant papers from 1958 to August 1997, identified through a MEDLINE search and from the bibliographies of articles identified.
The search identified 131 studies (99 prospective and 32 retrospective) involving a total of 10,694 patients. The patients' mean age was 57 yrs with no change over time. The overall mortality rate in the 131 studies was 49.7%. There was an overall significant trend of decreased mortality over the period studied (r=.49, p < .05). The mortality rate in those patients with bacteremia as an entry criterion was greater than that rate in patients whose entry criterion was sepsis without definite bacteremia (52.1% vs. 49.1%; chi2=6.1 and p< .05). The site of infection altered noticeably over the years. Chest-related infections increased over time, with Gram-negative infections becoming proportionately less common. If all other organisms and mixed infections are included with the Gram-positives, the result is more dramatic, with these organisms being causative in just 10% of infections between 1958 and 1979 but in 31% of infections between 1980 and 1997.
The present review showed a slight reduction in mortality from septic shock over the years, although this result should be approached with caution. The heterogeneity of the articles and absence of a severity score for most of the studies limited our analysis. Furthermore, there was an increasing prevalence of Gram-positive causative organisms, and a change of the predominant origin of sepsis from the abdomen to the chest.
HMG FUNCTIONAL MOTIFS The orderly progression of most DNA-related activities such as transcription, replication, recombination, and repair in- volves changes in the structure of the DNA and in the orga- nization of the chromatin fiber. Some of these structural changes are facilitated by a family of ubiquitous and abundant nonhistone nuclear proteins known as the high-mobility-group (HMG) proteins. In the narrowest traditional sense, the HMG protein family consists of six proteins and is subdivided into three subfamilies: the HMG-1/-2 subfamily, the HMG-I/Y sub- family and the HMG-14/-17 subfamily. These three HMG sub- families are similar in several physical characteristics (detailed reviews on these proteins are found in references 10, 12, 14, 28, and 54); however, each of the subfamilies has a unique protein signature and a characteristic functional sequence motif. These functional sequence motifs are the main site of interaction between the HMG proteins and the DNA or chromatin tar- gets. The HMG-1 domain (often referred to as the HMG-1 box) is the functional motif of the largest HMG subfamily, the HMG-1/-2 proteins; the AT hook is the functional motif of the HMG-I/Y group, and the nucleosomal binding domain is the functional motif of the HMG-14/-17 subfamily. Significantly, all of these functional motifs bind to specific structures in DNA or in chromatin, with little if any specificity for the target DNA sequence. All the HMG proteins are considered to function as architectural elements that modify the structure of DNA and chromatin to generate a conformation that facilitates and en- hances various DNA-dependent activities. The functional motifs characteristic of the HMG-1 (8, 10, 45, 61, 63) and HMG-I/Y (3, 51) subfamilies have been identified in numerous nuclear proteins that interact with DNA and chromatin. However, it is important to clearly distinguish the archetypal, or canonical, HMG proteins from the proteins con- taining these HMG motifs embedded in their primary se- quence. The former are ubiquitous in all the cells of higher eukaryotes, are relatively abundant, and bind to DNA in a sequence-independent fashion, while the latter are cell-type specific, are not abundant, bind to DNA in a sequence-specific fashion, and frequently contain additional, distinct non-HMG functional motifs. In considering the biological importance of the HMG mo- tifs, it is important to take into account their relative abun- dance in the nucleus. The cellular levels of HMG fluctuate; however, on the average, the amount of HMG-1/-2 in a cell is about 10-fold lower than that of a histone, the amount of HMG-14/-17 is 10-fold-lower than that of HMG-1/-2, and the amount of HMG-I/Y is 10-fold lower than that of HMG-14/-17 (54). The amount of HMG-14/-17 in the average cell, about 105 molecules, is sufficient to bind to 1% of the nucleosomes, i.e., to approximately 100,000 nucleosomes. Thus, even small fluc- tuations in the cellular levels of these abundant proteins may have significant biological consequences, since the expression of certain genes can be affected by structural changes in a single nucleosome (118, 119).
Amphoterin (HMG1) is a 30-kD heparin-binding protein which is functionally associated with the outgrowth of cytoplasmic processes in developing neurones. Amphoterin has been shown to mediate adhesive and proteolytic interactions at the leading edge of motile cells. Recently it was shown that inhibition of amphoterin interactions with its cell surface receptor (RAGE) suppresses tumour growth and metastasis. In this work we have identified amphoterin polypeptide and its mRNA in human platelets. Amphoterin had a cytoplasmic localisation in resting platelets according to subcellular fractionation studies and immunogold electronmicroscopy. After platelet activation, part of amphoterin was associated with the external surface of plasma membrane. Externalisation of amphoterin during platelet activation was also detected in immunofluorescence studies. Amphoterin was detectable in human serum (0.2 ng/ml) but not in plasma. Resting platelets treated with PGI2 and forskolin bound to immobilised recombinant amphoterin independently of divalent cations. The binding induced a spicular morphology in platelets, and was effectively inhibited by heparin. Amphoterin-binding protein components on the platelet surface were not identified, but amphoterin bound to phosphatidylserine and sulfatide in lipid binding assays. Our results suggest that amphoterin is an endogenous protein in human platelets, which is exported to the cell surface during platelet activation. Interaction of amphoterin with the platelet surface may be mediated by sulfoglycolipids and phospholipids.
We review the case definition, occurrence, and outcome of sepsis. We discuss whether the epidemiology of sepsis has changed over time and discuss issues important to our understanding of sepsis.
Literature review.
Our understanding of the epidemiology of sepsis is hampered by the lack of a reliable case definition. Inconsistent application of sepsis definition criteria contributes to confusion and variability in the literature. Variability in the time course of sepsis also introduces difficulty. The Centers for Disease Control estimated an incidence of 73.6 per 100,000 population in 1979, rising to 175.9 per 100,000 in 1989. However, this study was of septicemia, not severe sepsis. There are several hospital-based studies of the occurrence of severe sepsis, defined using the American College of Chest Physicians/Society of Critical Care Medicine consensus criteria. These studies reported variable hospital and intensive care unit (ICU) occurrence rates, ranging from 2% to 11% of all hospital or ICU admissions. Most of these data are from academic, tertiary care centers, which limits generalizability. More population-based studies are required to better delineate the incidence and risk factors of sepsis in the general population. Hospital mortality from sepsis has ranged from 25% to 80% over the last few decades. Although mortality may be lower in recent years, sepsis is clearly still a very serious condition. Achieving a better understanding of whether the mortality rate for sepsis is falling, however, is confounded by the lack of a uniform definition. Risk factors for adverse outcome include the degree of physiologic derangement, organ dysfunction, underlying illness, site of infection, and microbiological etiology. We do not know, however, the factors that predict response to new therapies. This dilemma has led researchers to explore whether markers of the inflammatory cascade might be more specific for sepsis, more accurate for risk prediction, or more useful for predicting response to therapy. However, there as yet is no equivalent of the CPK-MB for acute myocardial infarction. Whether we will find such a marker as we develop a greater understanding of the genetic control of the inflammatory cascade is uncertain but promising. One might assume intuitively that the epidemiology of sepsis is changing. For example, the number of patients being treated in ICUs has increased over time, the technologies used in the ICU have changed, and the choice and the use of antibiotics have changed. Predisposing factors, such as chemotherapeutic regimens, have also changed, and there have been marked changes in antibiotic resistance. Furthermore, there have been wide changes in the microbiological etiologies of diseases such as pneumonia and acute exacerbations of chronic bronchitis. However, lacking good case definitions and true incidence studies, we can only make inferences about whether the epidemiology of sepsis is truly changing.
Many studies have documented many aspects of the epidemiology of sepsis. However, the composite picture they provide, although rich in many aspects, remains incomplete and emphasizes the heterogeneity of the condition. Unfortunately, few population-based prospective cohort studies exist that allow us to accurately delineate the risk factors for sepsis, its course, and its outcome. To place new information, such as the role of genetic predisposition, in the correct context, it is essential that such studies be conducted.
To evaluate whether administration of afelimomab, an anti-tumor necrosis factor F(ab')2 monoclonal antibody fragment, would reduce 28-day all-cause mortality in patients with severe sepsis and elevated serum levels of IL-6.
Prospective, randomized, double-blind, placebo-controlled, multiple-center, phase III clinical trial.
One hundred fifty-seven intensive care units in the United States and Canada.
Subjects were 2,634 patients with severe sepsis secondary to documented infection, of whom 998 had elevated interleukin-6 levels.
Patients were stratified into two groups by means of a rapid qualitative interleukin-6 test kit designed to identify patients with serum interleukin-6 levels above (test positive) or below (test negative) approximately 1000 pg/mL. Of the 2,634 patients, 998 were stratified into the test-positive group, 1,636 into the test-negative group. They were then randomly assigned 1:1 to receive afelimomab 1 mg/kg or placebo for 3 days and were followed for 28 days. The a priori population for efficacy analysis was the group of patients with elevated baseline interleukin-6 levels as defined by a positive rapid interleukin-6 test result.
In the group of patients with elevated interleukin-6 levels, the mortality rate was 243 of 510 (47.6%) in the placebo group and 213 of 488 (43.6%) in the afelimomab group. Using a logistic regression analysis, treatment with afelimomab was associated with an adjusted reduction in the risk of death of 5.8% (p = .041) and a corresponding reduction of relative risk of death of 11.9%. Mortality rates for the placebo and afelimomab groups in the interleukin-6 test negative population were 234 of 819 (28.6%) and 208 of 817 (25.5%), respectively. In the overall population of interleukin-6 test positive and negative patients, the placebo and afelimomab mortality rates were 477 of 1,329 (35.9%)and 421 of 1,305 (32.2%), respectively. Afelimomab resulted in a significant reduction in tumor necrosis factor and interleukin-6 levels and a more rapid improvement in organ failure scores compared with placebo. The safety profile of afelimomab was similar to that of placebo.
Afelimomab is safe, biologically active, and well tolerated in patients with severe sepsis, reduces 28-day all-cause mortality, and attenuates the severity of organ dysfunction in patients with elevated interleukin-6 levels.
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