Table 2
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Despite 50 years of extensive research, no definite drug is currently available to treat acute respiratory distress syndrome (ARDS), and the supportive therapies remain the mainstay of treatment. To improve drug development for ARDS, researchers need to deeply analyze the "omics" approaches, reevaluate the suitable therapeutic targets, resolve the...
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Citations
... We measured organ dysfunction by monitoring changes in Sequential Organ Failure Assessment (SOFA) scores that an increase in score of 2 points or more was considered indicative of dysfunction [21]. To diagnose ARDS, we followed specific criteria: 1) severe hypoxemia (PaO 2 /FiO 2 ≤ 300 mmHg), 2) acute symptoms that developed within a week, 3) bilateral radiographic abnormalities (not attributable to atelectasis), and 4) The disorder was not caused by heart failure [22]. Meanwhile, we diagnosed SCM based on three criteria as follows: First, the patient had been diagnosed with sepsis; Second, the patient had one of the following three ultrasound abnormalities: A) left ventricular systolic mitral annulus velocity (LV-Sm) < 8 cm/s or Left Ventricular Ejection Fractions (LVEF) < 50%; B) Right ventricular systolic mitral annulus velocity (RV-Sm) < 12 cm/s; or C) peak early diastolic transmitral flow velocity/peak early diastolic mitral annular velocity (E/e') > 15 or peak early diastolic mitral annular velocity (e') < 8 cm/s; Third, the patient had no history of chronic heart disease, including coronary heart disease, chronic heart failure, regional ventricular wall motion abnormality, dilated cardiomyopathy, hypertrophic obstructive cardiomyopathy, congenital heart disease, or heart valve disease [23]. ...
Background
We aimed to assess the efficacy of the neutrophil elastase inhibitor, sivelestat, in the treatment of sepsis-induced acute respiratory distress syndrome (ARDS) and septic cardiomyopathy (SCM).
Methods
Between January 2019 and December 2021, we conducted a randomized trial on patients who had been diagnosed with sepsis-induced acute respiratory distress syndrome (ARDS) and septic cardiomyopathy (SCM) at Wuhan Union Hospital. The patients were divided into two groups by random envelop method, the Sivelestat group and the Control group. We measured the serum concentrations of Interleukin (IL)-6, IL-8, Tumor necrosis factor-α (TNF-α), and High-mobility group box 1 (HMGB1) at five time points, which were the baseline, 12 h, 24 h, 48 h, and 72 h after admission to the ICU. We evaluated the cardiac function by sonography and the heart rate variability (HRV) with 24-hour Holter recording between the time of admission to the intensive care unit (ICU) and 72 h after Sivelestat treatment.
Results
From January 2019 to December 2021, a total of 70 patients were included in this study. The levels of IL-6, IL-8, and TNF-α were significantly lower in the Sivelestat group at different time points (12 h, 24 h, 48 h, and 72 h). HMGB1 levels were significantly lower at 72 h after Sivelestat treatment (19.46 ± 2.63pg/mL vs. 21.20 ± 2.03pg/mL, P = 0.003). The stroke volume (SV), tricuspid annular plane systolic excursion (TAPSE), early to late diastolic transmitral flow velocity (E/A), early (e’) and late (a’) diastoles were significantly low in the Control group compared with the Sivelestat group. Tei index was high in the Control group compared with the Sivelestat group (0.60 ± 0.08 vs. 0.56 ± 0.07, P = 0.029). The result of HRV showed significant differences in standard deviation of normal-to-normal intervals (SDNN), low frequency (LF), and LF/HF (high frequency) between the two groups.
Conclusions
Sivelestat can significantly reduce the levels of serum inflammatory factors, improve cardiac function, and reduce heart rate variability in patients with Sepsis-induced ARDS and SCM.
... The results of this study also showed that the levels of peripheral blood CD3+, CD4+ and CD4+/CD8+ in the experimental group were significantly higher than those in the control group after treatment, and the differences were statistically significant. It shows that the cal activity [24]. Prolonged QTd indicates that the refractory period of cardiac myocytes in different parts is shortened or prolonged, leading to increased repolarization difference of ventricular myocytes, which easily leads to abnormal conduction and reentry, inducing malignant arrhythmia or sudden cardiac death, so it is of great significance in predicting the occurrence of malignant arrhythmia [25]. ...
Background:
This study aimed to investigate the effect of ulinastatin on myocardial protection in children with severe pneumonia.
Methods:
In this retrospective study, children with severe pneumonia were divided into two groups based on their treatment methods. The control group (n=39) received anti-infection therapy, while the experimental group (n=43) received anti-infection therapy combined with ulinastatin. The clinical treatment efficacy, levels of peripheral inflammatory factors, T lymphocyte subsets, QT dispersion and adverse reactions of the two groups were observed and compared before and after treatment.
Results:
The clinical efficacy was improved after intervention (P<0.05), and the total response rate was 88.4% (38/43) in the experimental group and 64.1% in the control group. The post-treatment levels of interleukin-8 (IL-8), interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) in the peripheral blood were lower than those before treatment, with significant differences (P<0.05). After treatment, the serum levels of CD3+, CD4+ and CD4+/CD8+ in the experimental group were significantly higher than those in the control group, whereas the levels of IL-6, IL-8 and hscRP in the peripheral blood were lower in the experimental group than those in the control group, with significant differences (P<0.05). The QT dispersion indexes, such as QTmax, QTmin, QTd, QTcmax, QTcd and QTcmin in the experimental group were shorter than those in the control group (P<0.05).
Conclusion:
Ulinastatin has significant therapeutic efficacy and safety in the clinical treatment of children with severe pneumonia, which may be related to inhibition of the release of inflammatory factors, shortened QT dispersion and the improvement of immune function of peripheral blood T lymphocyte subsets.
... ARDS is manifested by increased alveolar-capillary membrane permeability, neutrophil aggregation, compromised surfactant formation and edema that leads to reduced respiratory compliance and lifethreatening hypoxemia [1]. ARDS complications include pulmonary hypertension, intravascular coagulation, cognitive problems, muscle weakness [2], and cardiovascular diseases [3]. The mortality rate is high (26-61.5 ...
Acute respiratory distress syndrome (ARDS), a serious manifestation of acute lung injury (ALI), is a debilitating inflammatory lung disease that is caused by multiple risk factors. One of the primary causes that can lead to ALI/ARDS is cigarette smoke (CS) and its primary mode of action is via oxidative stress. Despite extensive research, no appropriate therapy is currently available to treat ALI/ARDS, which means there is a dire need for new potential approaches. In our study we explored the protective effects of 70 % methanolic-aqueous extract of Ipomoea nil (Linn.) Roth, named as In.Mcx against CS-induced ALI mice models and RAW 264.7 macrophages because Ipomoea nil has traditionally been used to treat breathing irregularities. Male Swiss albino mice (20–25 ± 2 g) were subjected to CS for 10 uninterrupted days in order to establish CS-induced ALI murine models. Dexamethasone (1 mg/kg), In.Mcx (100 200, and 300 mg/kg) and normal saline (10 mL/kg) were given to respective animal groups, 1 h before CS-exposure. 24 h after the last CS exposure, the lungs and bronchoalveolar lavage fluid (BALF) of all euthanized mice were harvested. Altered alveolar integrity and elevated lung weight-coefficient, total inflammatory cells, oxidative stress, expression of pro-inflammatory cytokines (IL-1β and IL-6) and chemokines (KC) were significantly decreased by In.Mcx in CS-exposed mice. In.Mcx also revealed significant lowering IL-1β, IL-6 and KC expression in CSE (4 %)-activated RAW 264.7 macrophage. Additionally, In.Mcx showed marked enzyme inhibition activity against Acetylcholinesterase, Butyrylcholinesterase and Lipoxygenase. Importantly, In.Mcx dose-dependently and remarkably suppressed the CS-induced oxidative stress via not only reducing the MPO, TOS and MDA content but also improving TAC production in the lungs. Accordingly, HPLC analysis revealed the presence of many important antioxidant components. Finally, In.Mcx showed a marked decrease in the NF-κB expression both in in vivo and in vitro models. Our findings suggest that In.Mcx has positive therapeutic effects against CS-induced ALI via suppressing uncontrolled inflammatory response, oxidative stress, lipoxygenase and NF-κB p65 pathway.
... TCM believes that qi deficiency and blood stasis are the basic pathogenesis of gastrointestinal dysfunction in ARDS patients treated with mechanical ventilation. Effective pharmacotherapy can be crucial in the treatment and prognosis of ARDS to enhance survival and shorten mechanical ventilation time [5]. Breztri Aerosphere, composed of budesonide/glycopyrronium bromide/formoterol, is a triple combination of the glucocorticoid budesonide, the longacting β2 agonist formoterol fumarate, and the long-acting cholinergic receptor antagonist glycopyrronium bromide [6]. ...
Objective:
To examine the clinical efficacy of budesonide/glycopyrronium bromide/formoterol (Breztri Aerosphere) as an adjunct to acute respiratory distress syndrome (ARDS).
Methods:
A prospective study enrolled 120 patients with pulmonary endogenous ARDS admitted to the Department of Critical Care Medicine at the Fourth Hospital of Baotou from January 2017 to January 2020, and all enrollments were assigned (1 : 1) to receive conventional treatment (control group) or Breztri Aerosphere (study group).
Results:
Breztri Aerosphere was associated with a significantly higher total efficacy versus conventional treatment. Breztri Aerosphere resulted in significantly lower acute physiology and chronic health evaluation scoring system (APACHE II) scores and Murray lung injury scores versus conventional treatment. Both groups saw an increase in the partial pressure of carbon dioxide (PCO2), partial pressure of oxygen (PO2), and oxygen saturation (SaO2) after treatment, with higher levels seen in patients given Breztri Aerosphere. After treatment, systemic vascular resistance (SVR) in both groups rose markedly, with greater elevation witnessed in the study group. The patients given Breztri Aerosphere showed significantly lower levels of pulmonary vascular resistance (PVR), mean pulmonary arterial pressure (MAPA), pulmonary artery wedge pressure (PAWP), interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), and procalcitonin (PCT) versus those receiving conventional treatment. The patients experienced shorter mechanical ventilation time and intensive care unit (ICU) time after treatment of Breztri Aerosphere versus conventional treatment.
Conclusion:
Adjuvant therapy with Breztri Aerosphere in ARDS can significantly lower APACHE II scores and Murray lung injury scores, improve blood gas indexes and pulmonary circulation function indexes, and shorten mechanical ventilation time and ICU time, which may be attributed to its improvement of organism inflammation status and reduction of inflammatory factors.
... Although the research into the pathophysiology of ARDS progresses in recent years, the molecular mechanisms of sepsis-induced ARDS remain to be fully elucidated [4]. On the other hand, in spite of several decades of efforts, there is still a lack of effective pharmacologic interventions to ARDS [5]. The most commonly used medications for ARDS are neuromuscular blocking agents [6], which only functions as an adjuvant to prevent ventilation-related lung injury. ...
Sepsis-induced acute respiratory distress syndrome (ARDS) remains a major threat to human health without effective therapeutic drugs. Previous studies demonstrated the power of gene expression profiling to reveal pathological changes associated with sepsis-induced ARDS. However, there is still a lack of systematic data mining framework for identifying potential targets for treatment. In this study, we demonstrated the feasibility of druggable targets prediction based on gene expression data. Through the functional enrichment analysis of microarray-based expression profiles between sepsis-induced ARDS and non-sepsis ARDS samples, we revealed genes involved in anti-microbial infection immunity were significantly altered in sepsis-induced ARDS. Protein–protein interaction (PPI) network analysis highlighted TOP2A gene as the key regulator in the dysregulated gene network of sepsis-induced ARDS. We were also able to predict several therapeutic drug candidates for sepsis-induced ARDS using Connectivity Map (Cmap) database, among which doxorubicin was identified to interact with TOP2A with a high affinity similar to its endogenous ligand. Overall, our findings suggest that doxorubicin could be a potential therapeutic for sepsis-induced ARDS by targeting TOP2A, which requires further investigation and validation. The whole study relies on publicly available dataset and publicly accessible database or bioinformatic tools for data mining. Therefore, our study benchmarks a workflow for druggable target prediction which can be widely applicable in the search of targets in other pathological conditions.
... Pulmonary edema can be cardiogenic or non-cardiogenic [15]; the latter occurs as a result of increased microvascular permeability and alveolar fluid infiltration [16]. General drug-induced ARDS is caused by chemical injury of the vascular endothelium and epithelium, which triggers hypoxia and pulmonary vascular resistance by the accumulation of protein-rich substances in the alveoli [17,18]. The etiology of MRI contrast agent-induced pulmonary edema is largely unknown; however, some hypothesized mechanisms include endothelial injury triggered by the activation of the complement system and direct chemical stimulation of the alveoli [16,17]. ...
... General drug-induced ARDS is caused by chemical injury of the vascular endothelium and epithelium, which triggers hypoxia and pulmonary vascular resistance by the accumulation of protein-rich substances in the alveoli [17,18]. The etiology of MRI contrast agent-induced pulmonary edema is largely unknown; however, some hypothesized mechanisms include endothelial injury triggered by the activation of the complement system and direct chemical stimulation of the alveoli [16,17]. ...
Rapid decline of pulmonary function in acute respiratory distress syndrome (ARDS) can make ARDS a dangerous and potentially life-threatening condition. Gadolinium-based contrast agents are considered safe alternatives to iodine-based contrast agents, with comparatively fewer adverse effects and a lower incidence of serious adverse events, such as dyspnea or hypotension. There are five reported cases of gadolinium-induced ARDS. A 59-year-old woman with respiratory failure 30 min after gadolinium administration was diagnosed with ARDS; she was admitted to the intensive care unit. Her condition improved by artificial respiration management and adrenaline and steroids administration. She was discharged on day 13. Considering ARDS occurred 30 min after gadolinium administration and findings suggesting anaphylaxis, such as wheezing and failure in organs other than the lungs, were absent, the involvement of any immediate-onset reaction was excluded; thus, a diagnosis of gadolinium-induced ARDS was made.
... 118 So far, no pharmacological therapies have reduced ARDS mortality, including those aimed at attenuating inflammation, preventing or suppressing fibrosis, addressing infection, or surfactant replacement to reduce fluid mechanical stress. 46,64,67 B. ARDS pathophysiology Pathophysiology of ARDS occurs in 3 chronological phases. In the exudative phase, severe inflammation causes diffuse alveolar injury and increased epithelial and microvascular permeability. ...
Complex in vitro models of the tissue microenvironment, termed microphysiological systems, have enormous potential to transform the process of discovering drugs and disease mechanisms. Such a paradigm shift is urgently needed in acute respiratory distress syndrome (ARDS), an acute lung condition with no successful therapies and a 40% mortality rate. Here, we consider how microphysiological systems could improve understanding of biological mechanisms driving ARDS and ultimately improve the success of therapies in clinical trials. We first discuss how microphysiological systems could explain the biological mechanisms underlying the segregation of ARDS patients into two clinically distinct phenotypes. Then, we contend that ARDS-mimetic microphysiological systems should recapitulate three critical aspects of the distal airway microenvironment, namely, mechanical force, inflammation, and fibrosis, and we review models that incorporate each of these aspects. Finally, we recognize the substantial challenges associated with combining inflammation, fibrosis, and/or mechanical force in microphysiological systems. Nevertheless, complex in vitro models are a novel paradigm for studying ARDS, and they could ultimately improve patient care.
... The most characteristic pathological features of ALI/ARDS include increased pulmonary vascular permeability and edema, inappropriate recruitment of alveolar macrophages and pulmonary neutrophils, uncontrolled secretion of pro-inflammatory mediators, surfactant dysfunction, impaired gas exchange, and subsequent respiratory failure owing to progressive and refractory hypoxemia [1]. Despite decades of extensive research, ALI/ARDS remain a major cause of morbidity and mortality in critically ill patients, with 10% prevalence in intensive care units (ICU) and 40-46% mortality [2], and no definite pharmacological agent is available yet [3]. However, scarce pharmacological options for ALI present an unrelenting challenge in the field of drug development. ...
Aims
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), characterized by overwhelming lung inflammation, are associated with high mortality. Cigarette smoke (CS) is one of the major causes of ALI/ARDS. Since high expression of prostaglandin (PG) D2 has been observed in CS-induced lung injury. Currently, no effective pharmacological therapies are available to treat ALI, and supportive therapies remain the mainstay of treatment. Therefore, we investigated the protective effect of CT‑133, a newly discovered selective CRTH2 antagonist, on CS-induced ALI in vivo and in vitro.
Main methods
CT‑133 (10 and 30 mg/kg), dexamethasone (1 mg/kg) and normal saline were intratracheally administrated 1 hr prior to whole-body CS-exposure for seven consecutive days to study the key characteristics of ALI. Subsequently, CSE (4%)- and PGD2-stimulated RAW 264.7 macrophages were used to evaluate the protective effect of CT‑133.
Key findings
CT‑133 remarkably attenuated infiltration of inflammatory cells, neutrophils, and macrophages in the BALF, albumin contents, expression of IL‑1β, IL‑6, TNF‑α and KC, lung myeloperoxidase (MPO) activity and lung histopathological alterations caused by CS exposure in mice. Moreover, CT‑133 not only reversed the uncontrolled secretion of IL‑1β, IL-6, TNF‑α and KC from CSE- and PGD2-stimulated RAW 264.7 macrophages but also augmented IL-10 production in both in vivo and in vitro studies. Additionally, CT‑133 alleviated in vitro neutrophil migration chemoattracted by PGD2.
Significance
Our results provide the first evidence that targeting CRTH2 could be a new potential therapeutic option to treat CS-induced ALI.
... In drug-induced ARDS, vascular endothelial and epithelial damage caused by the drug leads to the accumulation of protein-rich material in the alveoli, causing hypoxia and a subsequent increase in pulmonary vascular resistance. A complex series of events including neutrophilmediated damage, cytokine-induced inflammation, oxidant-mediated damage, and dysregulation of the coagulation and fibrinolytic pathways also play a role in the development of ARDS [8,9]. ...
Acute respiratory distress syndrome (ARDS) is a life-threatening medical emergency. The etiology of ARDS can involve various causes. ARDS associated with the use of iodinated contrast media is rarely reported, and the literature includes only one case of ARDS due to gadobutrol. A 46-year-old female patient presented to our emergency department with shortness of breath, wheezing, swelling of the lips, and difficulty swallowing about 30 minutes after undergoing magnetic resonance imaging with 6.5 ml (0.1 ml/kg) gadobutrol (Gadovist) contrast for a submandibular mass. She was treated for anaphylaxis, then immediately evaluated using chest x-ray and arterial blood gas analysis. Based on the findings, she was diagnosed with ARDS and started on continuous positive airway pressure (CPAP) ventilatory support and methylprednisolone at a dose of 1 mg/kg/day. On day 3 of follow-up, all symptoms had completely regressed. Keywords: ARDS, Contrast agent, Gadolinium
... No single explanation can resolve these discrepancies. 137 For example, in vitro experiments cannot capture or mimic the in vivo environment. ...
Type 2 diabetes mellitus is now a worldwide health problem with increasing prevalence. Mounting efforts have been made to treat, prevent and predict this chronic disease. In recent years, increasing evidence from mice and clinical studies suggest that bone‐derived molecules modulate glucose metabolism. This review aims to summarize our current understanding of the interplay between bone and glucose metabolism and highlight potential new means for therapeutic intervention. The first molecule recognized as a link between bone and glucose metabolism in mice is osteocalcin, which functions in its active form, i.e., undercarboxylated OCN (ucOC). ucOC acts in promoting insulin expression and secretion, facilitating insulin sensitivity, and favoring glucose and fatty acid uptake and utilization. A second bone‐derived molecule, lipocalin2, functions in suppressing appetite in mice through its action on the hypothalamus. Osteocytes, the most abundant cells in bone matrix, are suggested to act on the browning of white adipose tissue and energy expenditure through the secretion of bone morphogenetic protein 7 and sclerostin. The involvement of bone resorption in glucose homeostasis has also been examined. However, there is evidence indicating the implication of receptor activator of nuclear factor κ‐B ligand, neuropeptide Y, and other know and unidentified bone‐derived factors functioning in glucose homeostasis. We summarize recent advances and the rationale of treating, preventing, and predicting diabetes by skeleton intervention.
