Figure 1 - uploaded by Matthew J Delano
Content may be subject to copyright.
Earlier Conceptual View and Definition of Systemic Inflammatory Response Syndrome (SIRS), Sepsis, Severe Sepsis, and Septic Shock
Source publication
Sepsis occurs when an infection exceeds local tissue containment and induces a series of dysregulated physiologic responses that result in organ dysfunction. A subset of patients with sepsis progress to septic shock, defined by profound circulatory, cellular, and metabolic abnormalities, and associated with a greater mortality. Historically, sepsis...
Similar publications
Importance
The World Health Organization recommends exclusive breastfeeding for 6 months. However, 75% of British mothers introduce solids before 5 months and 26% report infant waking at night as influencing this decision.
Objective
To determine whether early introduction of solids influences infant sleep.
Design, Setting, and Participants
The En...
Global data indicate that cervical cancer is the fourth most common cancer among women worldwide. Important
factors that affect interventions for early diagnosis of cervical cancer include social beliefs and values and poor
knowledge. These may contribute to women’s participation in screening for cervical cancer and have a significant
impact on dec...
Background:
Attention to nutrition during all phases of child and adolescent development is necessary to ensure healthy physical growth and to protect investments made earlier in life. Leveraging school meals programs as platforms to scale-up nutrition interventions is relevant as programs function in nearly every country in the world.
Objective:...
The current study examined whether the vocabulary skills of sequential bilingual children who learned Cantonese as a home language (L1) and English as a second language (L2) were predicted by the amount of L1 and L2 used at home. Ninety-two preschool children who learned Cantonese as L1 were recruited from a Head Start program. The amounts of L1 an...
Background:
Obstetric fistula is a debilitating condition resulted from poorly (un) managed prolonged obstructed labor. It has significant psychosocial and economic consequences on those affected and their families. Data regarding experiences and coping mechanisms of Ethiopian women with fistula is scarce.
Methods:
Qualitative design was employe...
Citations
... Sepsis stands as a critical medical challenge marked by an aberrant immune response to infection, presenting a substantial danger to life [1,2]. This syndrome manifests as uncontrolled inflammation, often resulting in multiorgan dysfunction, notably affecting the lungs [1,2]. ...
... Sepsis stands as a critical medical challenge marked by an aberrant immune response to infection, presenting a substantial danger to life [1,2]. This syndrome manifests as uncontrolled inflammation, often resulting in multiorgan dysfunction, notably affecting the lungs [1,2]. According to Rudd et al., in 2017 alone, there were approximately 50 million reported cases of sepsis worldwide, with over 10 million deaths attributed to the condition, representing nearly 20% of all global fatalities [3]. ...
This study compared the therapeutic effects of engineered exosomes derived from RAW264.7 cells overexpressing hsa-let-7i-5p (engineered exosomes) to exosomes from human placenta-derived mesenchymal stem cells (hpMSC exosomes) against sepsis-induced acute lung injury. Adult male C57BL/6 mice were divided into lipopolysaccharide (LPS), LPS plus engineered exosome (LEExo), or LPS plus hpMSC exosome (LMExo) groups, alongside control groups. The results showed that lung injury scores (based on pathohistological characteristics) and the levels of lung function alterations, tissue edema, and leukocyte infiltration in LEExo and LMExo groups were comparable and significantly lower than in the LPS group (all p < 0.05). Furthermore, the levels of inflammation (nuclear factor-κB activation, cytokine upregulation), macrophage activation (hypoxia-inducible factor-1α activation, M1 phase polarization), oxidation, and apoptosis were diminished in LEExo and LMExo groups compared to the LPS group (all p < 0.05). Inhibition of hsa-let-7i-5p attenuated the therapeutic effects of both engineered and hpMSC exosomes. These findings underscore the potent therapeutic capacity of engineered exosomes enriched with hsa-let-7i-5p and their potential as an alternative to hpMSC exosomes for sepsis treatment. Continued research into the mechanisms of action and optimization of engineered exosomes could pave the way for their future clinical application.
... At its core, sepsis begins as a response to infection. The immune system, activated by the presence of pathogens, initiates a series of signalling pathways aimed at eradicating the invaders [11,12]. However, in sepsis, this response spirals out of control, triggering a systemic inflammatory response syndrome that can lead to widespread tissue damage [13]. ...
... Sepsis arises when the body's immune response to an infection becomes uncontrolled, leading to widespread inflammation and organ dysfunction [10,11,12]. TLR2, by recognizing specific molecular patterns on bacterial pathogens, plays a pivotal role in triggering the immune response [8]. ...
... Previous studies have demonstrated the close connection between sepsis and immune microenvironment (Delano and Ward, 2016;Liu et al., 2022). Therefore, we assessed the concrete changes in immune microenvironment using CIBERSORT ( Figure 4A). ...
Introduction
Sepsis leads to multi-organ dysfunction due to disorders of the host response to infections, which makes diagnosis and prognosis challenging. Apoptosis, a classic programmed cell death, contributes to the pathogenesis of various diseases. However, there is much uncertainty about its mechanism in sepsis.
Methods
Three sepsis gene expression profiles (GSE65682, GSE13904, and GSE26378) were downloaded from the Gene Expression Omnibus database. Apoptosis-related genes were obtained from the Kyoto Encyclopedia of Genes and Genomes Pathway database. We utilized LASSO regression and SVM-RFE algorithms to identify characteristic genes associated with sepsis. CIBERSORT and single cell sequencing analysis were employed to explore the potential relationship between hub genes and immune cell infiltration. The diagnostic capability of hub genes was validated across multiple external datasets. Subsequently, the animal sepsis model was established to assess the expression levels of hub genes in distinct target organs through RT-qPCR and Immunohistochemistry analysis.
Results
We identified 11 apoptosis-related genes as characteristic diagnostic markers for sepsis: CASP8, VDAC2, CHMP1A, CHMP5, FASLG, IFNAR1, JAK1, JAK3, STAT4, IRF9, and BCL2. Subsequently, a prognostic model was constructed using LASSO regression with BCL2, FASLG, IRF9 and JAK3 identified as hub genes. Apoptosis-related genes were closely associated with the immune response during the sepsis process. Furthermore, in the validation datasets, aside from IRF9, other hub genes demonstrated similar expression patterns and diagnostic abilities as observed in GSE65682 dataset. In the mouse model, the expression differences of hub genes between sepsis and control group revealed the potential impacts on sepsis-induced organ injury.
Conclusion
The current findings indicated the participant of apoptosis in sepsis, and apoptosis-related differentially expressed genes could be used for diagnosis biomarkers. BCL2, FASLG, IRF9 and JAK3 might be key regulatory genes affecting apoptosis in sepsis. Our findings provided a novel aspect for further exploration of the pathological mechanisms in sepsis.
... Recent findings suggest that immune dysfunction is a crucial factor in the progression of sepsis, as the majority of septic individuals have encountered instances of lymphopenia. However, the specific mechanisms that cause sepsis-induced immunosuppression at the cellular and molecular levels still need to be elucidated [7,8]. To aid in our understanding of the pathophysiological process of sepsis, it is significantly helpful to comprehend the alterations in different immune cell subsets in the setting of sepsis. ...
... Since sepsis-induced immunosuppression mediated by DC dysfunction is crucial for the prognosis of septic patients. In the past decades, there have been a number of immunemodulatory therapies that could impact DC function and survival, although they are not DC specific, including anti-PD-1, anti-PDL1, anti-FAS, anti-CTLA4, etc. [5,8,26,150,151]. Some of the clinical trials related to it are still ongoing. ...
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Studies have indicated that immune dysfunction plays a central role in the pathogenesis of sepsis. Dendritic cells (DCs) play a crucial role in the emergence of immune dysfunction in sepsis. The major manifestations of DCs in the septic state are abnormal functions and depletion in numbers, which are linked to higher mortality and vulnerability to secondary infections in sepsis. Apoptosis is the most widely studied pathway of number reduction in DCs. In the past few years, there has been a surge in studies focusing on regulated cell death (RCD). This emerging field encompasses various forms of cell death, such as necroptosis, pyroptosis, ferroptosis, and autophagy-dependent cell death (ADCD). Regulation of DC’s RCD can serve as a possible therapeutic focus for the treatment of sepsis. Throughout time, numerous tactics have been devised and effectively implemented to improve abnormal immune response during sepsis progression, including modifying the functions of DCs and inhibiting DC cell death. In this review, we provide an overview of the functional impairment and RCD of DCs in septic states. Also, we highlight recent advances in targeting DCs to regulate host immune response following septic challenge.
Graphical Abstract
... We cannot be certain of the cause(s) of the different recovery trajectories of the wombats in this study (e.g., reexposure, recrudescence, impacts of duration of infection, age of animal, and other health factors at the time of treatment). Continuous and severe infections may coalesce into a chronic state of immune suppression with persistent and reoccurring secondary infections (Delano and Ward 2016). This phenomenon could potentially explain why wombat 1 seemingly had an improved mange score in July and September 2021, but no substantial change in bacterial beta diversity, or relative abundance of Staphylococcus or Corynebacterium. ...
... Impaired organ function, specifically the cardiovascular system, can have a profound impact on the body's hemodynamic stability. When sepsis involves the heart, it can impact the heart ventricles negatively resulting in a high mortality rate and slow recovery (Delano & Ward, 2016). ...
... Catecholamines are known to play a pivotal role in the cardiovascular complications associated with sepsis (Drosatos et al., 2015). During sepsis, the sympathetic nervous system becomes highly activated, leading to the excessive release of stress hormones and proinflammatory cytokines, which can strain the heart (Delano & Ward, 2016). Additionally, the surge in catecholamine release can have detrimental effects on the heart and blood vessels, potentially affecting recovery and prolonging ICU length of stay (Gubbi et al., 2020). ...
Background
Septic shock is associated with systemic inflammatory response, hemodynamic instability, impaired sympathetic control, and the development of multiorgan dysfunction that requires vasopressor or inotropic support. The regulation of immune function in sepsis is complex and varies over time. However, activating Beta-2 receptors and blocking Beta-1 receptors reduces the proinflammatory response by influencing cytokine production. Evidence that supports the concomitant use of ultra short beta-blockers with inotropes and vasopressors in patients with septic shock is still limited. This study aimed to evaluate the use of ultra short beta-blockers and its impact on the ICU related outcomes such as mortality, length of stay, heart rate control, shock resolution, and vasopressors/inotropes requirements.
Methods
A systematic review and meta-analysis of randomized controlled trials including critically ill patients with septic shock who received inotropes and vasopressors. Patients who received either epinephrine or norepinephrine without beta-blockers “control group” were compared to patients who received ultra short beta-blockers concomitantly with either epinephrine or norepinephrine “Intervention group”. MEDLINE and Embase databases were utilized to systematically search for studies investigating the use of ultra short beta-blockers in critically ill patients on either epinephrine or norepinephrine from inception to October 10, 2023. The primary outcome was the 28-day mortality. While, length of stay, heart rate control, and inotropes/ vasopressors requirements were considered secondary outcomes.
Results
Among 47 potentially relevant studies, nine were included in the analysis. The 28-day mortality risk was lower in patients with septic shock who used ultra short beta-blockers concomitantly with either epinephrine or norepinephrine compared with the control group (RR (95%CI): 0.69 (0.53, 0.89), I2=26%; P=0.24). In addition, heart rate was statistically significantly lower with a standardized mean difference (SMD) of -22.39 (95% CI: -24.71, –20.06) among the beta-blockers group than the control group. The SMD for hospital length of stay and the inotropes requirement were not statistically different between the two groups (SMD (95%CI): -0.57 (-2.77, 1.64), and SMD (95%CI): 0.08 (-0.02, 0.19), respectively).
Conclusion
The use of ultra short beta-blockers concomitantly with either epinephrine or norepinephrine in critically ill patients with septic shock was associated with better heart rate control and survival benefits without increment in the inotropes and vasopressors requirement.
... Moreover, the chronic inflammatory state of hidradenitis suppurativa hinders wound healing, providing a continual entry point for bacteria and amplifying the risk of Fournier's gangrene development [10] . Once Fournier's gangrene is established, hidradenitis suppurativa's immune dysfunction [11] contributes to an excessive systemic inflammatory response, manifesting as widespread endothelial dysfunction, increased vascular permeability and potentially facilitating the progression to septic shock [12,13] . Treatment necessitates a tailored approach, including surgical debridement and personalised antibiotic therapy. ...
Background: Fournier’s gangrene represents a life-threatening necrotising infection affecting the perineal region, while hidradenitis suppurativa is characterised by a chronic inflammatory skin condition. The simultaneous occurrence of both conditions is exceedingly rare. Case description: A 42-year-old female with a documented history of severe untreated hidradenitis suppurativa presented for shortness of breath, fever and lethargy, along with extensive wounds and skin breakdown involving the left axilla, perineum, lower back, lumbosacral region and bilateral gluteal areas, extending to the perineum. Upon presentation, the patient was in a state of septic shock, and a diagnosis of actively manifesting Fournier’s gangrene was established at the site of the pre-existing hidradenitis suppurativa lesions. Despite the implementation of an aggressive multidisciplinary approach incorporating surgical interventions, antibiotic therapy and intensive care measures, the patient’s condition deteriorated, culminating in septic shock, multi-organ failure and eventual demise. In this report, we discuss both clinical entities, their similarities and differences, and the possible mechanisms by which they may have co-occurred. Conclusion: The co-existence of hidradenitis suppurativa and Fournier’s gangrene poses unique challenges, given the rapid progression of Fournier’s gangrene within the context of hidradenitis suppurativa, potentially suggesting the latter as a predisposing factor. This case underscores the importance of vigilant screening and management of hidradenitis suppurativa.
... 19 Numerous studies have indicated that uncontrolled macrophages activation is a key mechanism driving sepsis. 20,21 This is due to their widespread presence in various organs and their multifaceted roles, including antigen presentation, phagocytosis, and production of inflammatory cytokines. 22,23 Upon the initiation of sepsis, macrophages respond to inflammatory stimuli with heightened activity and morph into a pro-inflammatory phenotype. ...
... [13][14][15][16] It is increasingly evident that uncontrolled macrophage activation is a fundamental mechanism underlying sepsis. 20,21 Exhibiting remarkable phenotypic plasticity, macrophages can oscillate between pro-inflammatory M1 and antiinflammatory M2 states in response to varying environmental cues. 50 At the onset of sepsis, macrophages are excessively activated by inflammatory stimuli and differentiate into a pro-inflammatory M1 phenotype. ...
Sepsis, critical condition marked by severe organ dysfunction from uncontrolled infection, involves the endothelium significantly. Macrophages, through paracrine actions, play a vital role in sepsis, but their mechanisms in sepsis pathogenesis remain elusive. Objective: We aimed to explore how macrophage-derived exosomes with low miR-141 expression promote pyroptosis in endothelial cells (ECs). Exosomes from THP-1 cell supernatant were isolated and characterized. The effects of miR-141 mimic/inhibitor on apoptosis, proliferation, and invasion of Human Umbilical Vein Endothelial Cells (HUVECs) were assessed using flow cytometry, CCK-8, and transwell assays. Key pyroptosis-related proteins, including caspase-1, IL-18, IL-1β, NLR Family Pyrin Domain Containing 3 (NLRP3), ASC, and cleaved-GSDMD, were analyzed via Western blot. The interaction between miR-141 and NLRP3 was studied using RNAhybrid v2.2 and dual-Luciferase reporter assays. The mRNA and protein level of NLRP3 after exosomal miR-141 inhibitor treatment was detected by qPCR and Western blot, respectively. Exosomes were successfully isolated. miR-141 mimic reduced cell death and pyroptosis-related protein expression in HUVECs, while the inhibitor had opposite effects, increasing cell death, and enhancing pyroptosis protein expression. Additionally, macrophage-derived exosomal miR-141 inhibitor increased cell death and pyroptosis-related proteins in HUVECs. miR-141 inhibits NLRP3 transcription. Macrophages facilitate sepsis progression by secreting miR-141 decreased exosomes to activate NLRP3-mediated pyroptosis in ECs, which could be a potentially valuable target of sepsis therapy.
... Recent advances in sepsis research recognize and appreciate that many pathways are perturbed during sepsis development [8][9][10]. Regardless, immune dysregulation undoubtably remains a vital factor in the pathology of sepsis [11][12][13]. Because of this, we concluded our study by evaluating the predicted immune cell profile in our low and high sepsis survival scores and found that the predicted proportion of immune cells does indicate a delineation of immune dysregulation between the scores. ...
... Additionally, both upregulated and downregulated genes are enriched among the hematopoietic cell lineage pathway. Moreover, it is known that the immune system plays critical roles in the progression of sepsis, although the molecular mechanisms underlying immune dysregulation within sepsis are still poorly understood [11,12]; to remedy this, we investigated the proportion of immune cells in peripheral blood mononuclear cell (PBMC) to delineate immune dysregulation between sepsis high and low risk groups. Using CIBERSORT, we established a reference for estimated proportions of immune cells in PBMC ( Figure 5D). ...
... Additionally, both upregulated and downregulated genes are enriched among the hematopoietic cell lineage pathway. Moreover, it is known that the immune system plays critical roles in the progression of sepsis, although the molecular mechanisms underlying immune dysregulation within sepsis are still poorly understood [11,12]; to remedy this, we investigated the proportion of immune cells in peripheral blood mononuclear cell (PBMC) Lastly, to validate that our 37-gene signature performs significantly better than other combinations of gene signatures, we compared the diagnostic performance of this 37-gene signature with random gene signatures from the whole genome genes or only sepsis survival-related genes ( Figure 6) [15,16]. The sum of the 37-gene signature-based AUC value (1.88) in the discovery and validation cohort is better than over 95% of random gene signatures (10,000 randomly times selected 37 genes) selected from whole genome or sepsis survival-related genes. ...
Sepsis continues to overwhelm hospital systems with its high mortality rate and prevalence. A strategy to reduce the strain of sepsis on hospital systems is to develop a diagnostic/prognostic measure that identifies patients who are more susceptible to septic death. Current biomarkers fail to achieve this outcome, as they only have moderate diagnostic power and limited prognostic capabilities. Sepsis disrupts a multitude of pathways in many different organ systems, making the identification of a single powerful biomarker difficult to achieve. However, a common feature of many of these perturbed pathways is the increased generation of reactive oxygen species (ROS), which can alter gene expression, changes in which may precede the clinical manifestation of severe sepsis. Therefore, the aim of this study was to evaluate whether ROS-related circulating molecular signature can be used as a tool to predict sepsis survival. Here we created a ROS-related gene signature and used two Gene Expression Omnibus datasets from whole blood samples of septic patients to generate a 37-gene molecular signature that can predict survival of sepsis patients. Our results indicate that peripheral blood gene expression data can be used to predict the survival of sepsis patients by assessing the gene expression pattern of free radical–associated -related genes in patients, warranting further exploration.
... After the invasion of microorganisms into the body, an immune response is triggered to fight off the invading microorganisms. This causes inflammation, a normal and necessary response to promptly identify, eradicate, and keep the infection localized [54]. However, as shown in Fig. 1, the immune response is exaggerated during sepsis, resulting in collateral damage and death of host cells and tissues, compromising both the affected and distant organs and leading to functional abnormalities and lifethreatening multiorgan failure [55]. ...
Sepsis represents a critical medical condition stemming from an imbalanced host immune response to infections, which is linked to a significant burden of disease. Despite substantial efforts in laboratory and clinical research, sepsis remains a prominent contributor to mortality worldwide. Nanotechnology presents innovative opportunities for the advancement of sepsis diagnosis and treatment. Due to their unique properties, including diversity, ease of synthesis, biocompatibility, high specificity, and excellent pharmacological efficacy, peptides hold great potential as part of nanotechnology approaches against sepsis. Herein, we present a comprehensive and up-to-date review of the applications of peptides in nanosystems for combating sepsis, with the potential to expedite diagnosis and enhance management outcomes. Firstly, sepsis pathophysiology, antisepsis drug targets, current modalities in management and diagnosis with their limitations, and the potential of peptides to advance the diagnosis and management of sepsis have been adequately addressed. The applications have been organized into diagnostic or managing applications, with the last one being further sub-organized into nano-delivered bioactive peptides with antimicrobial or anti-inflammatory activity, peptides as targeting moieties on the surface of nanosystems against sepsis, and peptides as nanocarriers for antisepsis agents. The studies have been grouped thematically and discussed, emphasizing the constructed nanosystem, physicochemical properties, and peptide-imparted enhancement in diagnostic and therapeutic efficacy. The strengths, limitations, and research gaps in each section have been elaborated. Finally, current challenges and potential future paths to enhance the use of peptides in nanosystems for combating sepsis have been deliberately spotlighted. This review reaffirms peptides' potential as promising biomaterials within nanotechnology strategies aimed at improving sepsis diagnosis and management.
Graphical Abstract
