Application In Sepsis Research Articles

A comprehensive review of glycocalyx investigation and therapeutic applications in sepsis and septic shock

Abstract Background Sepsis is a global health challenge that causes more than 11 million deaths annually and represents a substantial medical and economic burden. With rising treatment costs and significant mortality rates associated with organ dysfunction and septic shock, research efforts have focused on investigating the mechanism of glycocalyx (GCX) degradation as well as its regenerative capacity. Therefore, GCX has become a target in therapeutic strategies. Methods We performed a comprehensive review of articles published in PubMed database between 2014 and 2024, in the English language, dealing with statistical data, morphological and physiological aspects of the GCX, pathophysiological mechanisms, in vivo and in vitro research methods, clinical and laboratory experiences, therapeutic strategies, and innovative methods of prevention, both in the context of sepsis and its associated complications. Results The database search identified 300 records on the topic. After title/abstract screening, 187 articles were assessed in full text for eligibility, including articles with additional topics addressing the main topic. Of these, a total of 70 studies were included. Conclusions Exploring the structure of GCX holds real potential in the diagnosis and treatment of sepsis and its complications. Current research focuses on understanding GCX degradation, correlating its components with sepsis severity, predicting disease progression, and evaluating the impact of therapeutic strategies on GCX components.

Cardiovascular effects of Roflumilast during sepsis: Risks or benefits?

BackgroundPhosphodiesterase-4 (PDE4) is responsible for terminating cyclic adenosine monophosphate (cAMP) signalling. PDE4 inhibitors, such as roflumilast (RFM), have anti-inflammatory activity and have been studied in inflammation-induced tissue damage in sepsis. However, the role of RFM on cardiovascular derangements induced by sepsis is still unknown. Thus, we aimed to evaluate the potential effects of RFM on cardiovascular collapse and multiorgan damage caused by sepsis. MethodsSepsis was induced by cecal ligation and puncture (CLP) in male rats. Six hours after the CLP or sham procedure, animals were randomly assigned to receive either RFM (0.3 mg/kg) or vehicle subcutaneously, and cardiovascular parameters were assessed 24 h after the surgery and organ/plasma samples were collected for further analyses. ResultsSepsis induced hypotension, tachycardia, reduced renal blood flow (RBF) and hyporeactivity to vasoconstrictors both in vivo and ex vivo. RFM treatment increased systemic cAMP levels and RBF. RFM also attenuated hypoperfusion and liver damage induced by CLP. Furthermore, RFM reduced systemic nitric oxide (NO) levels in septic rats, while there were no changes in hepatic NOS-2 expression. Nevertheless, RFM exacerbated sepsis-induced hypotension and tachycardia without ameliorating vascular hyporeactivity. ConclusionOur data show that PDE-4 inhibition protects septic rats from hepatic injury and improves renal perfusion. However, RFM worsened hemodynamic parameters and showed no protection against sepsis-induced cardiovascular dysfunction and mortality. Thus, despite the anti-inflammatory benefits of RFM, its application in sepsis should be approached cautiously.

Developments and Trends of Nanotechnology Application in Sepsis: A Comprehensive Review Based on Knowledge Visualization Analysis.

Sepsis, a common life-threatening clinical condition, continues to have high morbidity and mortality rates, despite advancements in management. In response, significant research efforts have been directed toward developing effective strategies. Within this scope, nanotechnology has emerged as a particularly promising field, attracting significant interest for its potential to enhance disease diagnosis and treatment. While several reviews have highlighted the use of nanoparticles in sepsis, comprehensive studies that summarize and analyze the hotspots and research trends are lacking. To identify and further promote the development of nanotechnology in sepsis, a bibliometric analysis was conducted on the relevant literature, assessing research trends and hotspots in the application of nanomaterials for sepsis. Next, a comprehensive review of the subjectively recognized research hotspots in sepsis, including nanotechnology-enhanced biosensors and nanoscale imaging for sepsis diagnostics, and nanoplatforms designed for antimicrobial, immunomodulatory, and detoxification strategies in sepsis therapy, is elucidated, while the potential side effects and toxicity risks of these nanomaterials were discussed. Particular attention is given to biomimetic nanoparticles, which mimic the biological functions of source cells like erythrocytes, immune cells, and platelets to evade immune responses and effectively deliver therapeutic agents, demonstrating substantial translational potential. Finally, current challenges and future perspectives of nanotechnology applications in sepsis with a view to maximizing their great potential in the research of translational medicine are also discussed.

Establishment of growth stimulating gene 2 protein time-resolved fluorescence immunoassay and its application in sepsis

AimThis study aimed to establish a highly sensitive time-resolved fluorescence immunoassay of growth stimulating express gene 2 protein (ST2-TRFIA) and evaluate its application value for sepsis. MethodsTwo types of ST2 monoclonal specific antibodies against different epitopes of antigen molecule were used as coating and Eu3+-labeled antibodies. The double-antibody sandwich method was used in establishing ST2-TRFIA, and the methodology was evaluated. The established ST2-TRFIA was used in detecting ST2 concentration in the plasma samples of healthy controls and sepsis. ResultsThe linear range of ST2-TRFIA was 1.446–500 ng/mL. Plasma ST2 concentrations detected through ST2-TRFIA were consistent with the results of fluorescence quantitative immunochromatography (ρ = 0.946). The plasma ST2 concentrations of patients with sepsis were significantly higher than those of healthy controls (P < 0.01). ConclusionThis study successfully established a highly sensitive ST2-TRFIA, which was highly comparable to commercially available fluorescent quantitative immunochromatographic kits and can facilitate the timely diagnosis of sepsis.

Nanotechnology Applications in Sepsis: Essential Knowledge for Clinicians.

Sepsis is a life-threatening condition caused by a dysregulated host response to an invading pathogen such as multidrug-resistant bacteria. Despite recent advancements, sepsis is a leading cause of morbidity and mortality, resulting in a significant global impact and burden. This condition affects all age groups, with clinical outcomes mainly depending on a timely diagnosis and appropriate early therapeutic intervention. Because of the unique features of nanosized systems, there is a growing interest in developing and designing novel solutions. Nanoscale-engineered materials allow a targeted and controlled release of bioactive agents, resulting in improved efficacy with minimal side effects. Additionally, nanoparticle-based sensors provide a quicker and more reliable alternative to conventional diagnostic methods for identifying infection and organ dysfunction. Despite recent advancements, fundamental nanotechnology principles are often presented in technical formats that presuppose advanced chemistry, physics, and engineering knowledge. Consequently, clinicians may not grasp the underlying science, hindering interdisciplinary collaborations and successful translation from bench to bedside. In this review, we abridge some of the most recent and most promising nanotechnology-based solutions for sepsis diagnosis and management using an intelligible format to stimulate a seamless collaboration between engineers, scientists, and clinicians.

Autophagy Regulation on Pyroptosis: Mechanism and Medical Implication in Sepsis.

Sepsis is defined as a life-threatening disease involving multiple organ dysfunction caused by dysregulated host responses to infection. To date, sepsis remains a dominant cause of death among critically ill patients. Pyroptosis is a unique form of programmed cell death mediated by the gasdermin family of proteins and causes lytic cell death and release of proinflammatory cytokines. Although there might be some positive aspects to pyroptosis, it is regarded as harmful during sepsis and needs to be restricted. Autophagy was originally characterized as a homeostasis-maintaining mechanism in living cells. In the past decade, its function in negatively modulating pyroptosis and inflammation during sepsis has attracted increased attention. Here, we present a comprehensive review of the regulatory effect of autophagy on pyroptosis during sepsis, including the latest advances in our understanding of the mechanism and signaling pathways involved, as well as the potential therapeutic application in sepsis.

Effect of inhibiting the activity of double-stranded RNA-dependent protein kinase in sepsis mice

Objective: To observe the effects of 2-aminopurine (2-AP), a double-stranded RNA-dependent protein kinase (PKR) inhibitor, on organ function, plasma inflammatory factor expression and 7 days mortality in sepsis mice induced by cecal ligation puncture (CLP). Methods: Forty specific specific pathogen free C57BL/6 mice were randomly divided into sham group (n=10), CLP group (n=10), CLP+2-AP group (n=10) and 2-AP group (n=10). CLP was used to establish sepsis mice models.Peripheral blood serum was collected 24 hours after operation, alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine (Cr), blood urea nitrogen (BUN) and inflammatory factors (IL-1β, IL-10 and TNF-α) were detected; peripheral blood and peritoneal lavage fluid were taken for bacterial clearance detection. Another 60 C57BL/6 mice were selected to observe the 7-day survival rate according to the above groups (n=15). Independent sample t test was used to compare the measurement data between groups. Results: The levels of ALT, AST, Cr and BUN in CLP Group and CLP+2-AP group were significantly higher than those in sham group (all P<0.001). The levels of ALT and AST in CLP+2-AP group were significantly lower than those in CLP Group (t=27.88, 11.33, both P<0.001); the levels of Cr and BUN in CLP+2-AP group were significantly lower than those in CLP Group (t=11.02, 7.15, bothP<0.001). Compared with sham group, the levels of pro-inflammatory (IL-1β and TNF-α) and anti-inflammatory (IL-10) cytokines in CLP group were significantly higher (all P<0.001); the levels of IL-1β and IL-10 in CLP+2-AP group were significantly lower (all P<0.001), but the levels of TNF-α in CLP+2-AP group were not significantly lower (P=0.33). The 7-day survival rate was 100% in sham group, 13.3% in CLP+2-AP group, 86.7% in 2-AP group and 20.0% in CLP+2-AP group. Inhibition of PKR activation slightly improved the trend of 7-days survival rate of CLP model mice (analysis by mantel Cox test, χ(2)=0.0012, P=0.97). Conclusion: In sepsis mice model, inhibition of PKR activity can reduce the expression of inflammatory factors in plasma, decrease bacterial load in blood and abdominal cavity, and protect organ function, which could suggest that inhibition of PKR activity has potential application in sepsis treatment.

A network-based algorithm for the identification of moonlighting noncoding RNAs and its application in sepsis.

Moonlighting proteins provide more options for cells to execute multiple functions without increasing the genome and transcriptome complexity. Although there have long been calls for computational methods for the prediction of moonlighting proteins, no method has been designed for determining moonlighting long noncoding ribonucleicacidz (RNAs) (mlncRNAs). Previously, we developed an algorithm MoonFinder for the identification of mlncRNAs at the genome level based on the functional annotation and interactome data of lncRNAs and proteins. Here, we update MoonFinder to MoonFinder v2.0 by providing an extensive framework for the detection of protein modules and the establishment of RNA-module associations in human. A novel measure, moonlighting coefficient, was also proposed to assess the confidence of an ncRNA acting in a moonlighting manner. Moreover, we explored the expression characteristics of mlncRNAs in sepsis, in which we found that mlncRNAs tend to be upregulated and differentially expressed. Interestingly, the mlncRNAs are mutually exclusive in terms of coexpression when compared to the other lncRNAs. Overall, MoonFinder v2.0 is dedicated to the prediction of human mlncRNAs and thus bears great promise to serve as a valuable R package for worldwide research communities (https://cran.r-project.org/web/packages/MoonFinder/index.html). Also, our analyses provide the first attempt to characterize mlncRNA expression and coexpression properties in adult sepsis patients, which will facilitate the understanding of the interaction and expression patterns of mlncRNAs.

A Review of Malaysian Herbal Plants and Their Active Constituents with Potential Therapeutic Applications in Sepsis.

Sepsis refers to organ failure due to uncontrolled body immune responses towards infection. The systemic inflammatory response triggered by pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS) from Gram-negative bacteria, is accompanied by the release of various proinflammatory mediators that can lead to organ damage. The progression to septic shock is even more life-threatening due to hypotension. Thus, sepsis is a leading cause of death and morbidity globally. However, current therapies are mainly symptomatic treatment and rely on the use of antibiotics. The lack of a specific treatment demands exploration of new drugs. Malaysian herbal plants have a long history of usage for medicinal purposes. A total of 64 Malaysian plants commonly used in the herbal industry have been published in Malaysian Herbal Monograph 2015 and Globinmed website (http://www.globinmed.com/). An extensive bibliographic search in databases such as PubMed, ScienceDirect, and Scopus revealed that seven of these plants have antisepsis properties, as evidenced by the therapeutic effect of their extracts or isolated compounds against sepsis-associated inflammatory responses or conditions in in vitro or/and in vivo studies. These include Andrographis paniculata, Zingiber officinale, Curcuma longa, Piper nigrum, Syzygium aromaticum, Momordica charantia, and Centella asiatica. Among these, Z. officinale is the most widely studied plant and seems to have the highest potential for future therapeutic applications in sepsis. Although both extracts as well as active constituents from these herbal plants have demonstrated potential antisepsis activity, the activity might be primarily contributed by the active constituent(s) from each of these plants, which are andrographolide (A. paniculata), 6-gingerol and zingerone (Z. officinale), curcumin (C. longa), piperine and pellitorine (P. nigrum), biflorin (S. aromaticum), and asiaticoside, asiatic acid, and madecassoside (C. asiatica). These active constituents have shown great antisepsis effects, and further investigations into their clinical therapeutic potential may be worthwhile.

Effects of FM0807, a novel curcumin derivative, on lipopolysaccharide-induced inflammatory factor release via the ROS/JNK/p53 pathway in RAW264.7 cells

Purpose: Sepsis is a systemic inflammatory response caused by infection. Curcumin is known to have antioxidant and anti-inflammatory activities. FM0807, a curcumin derivative, was investigated in the present study to determine its effect on cytokines and the possible molecular mechanism. Main methods: The experiments were carried out in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Cell viability was measured by MTT assay. ELISA, Griess assays, fluorescence-based quantitative PCR, flow cytometric analysis, 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) experiments, and Western blotting were carried out to assess the potential effects of FM0807 on LPS-induced RAW 264.7 cells. Significant findings: FM0807 had no cytotoxic effects on RAW 264.7 cells. Furthermore, pretreatment with FM0807 inhibited the inflammatory factor tumor necrosis factor-α (TNF-α), interleukin (IL) 1β (IL-1β), IL-6, and inducible nitric oxide synthase (iNOS) at the protein and gene levels. FM0807 also inhibited the production of reactive oxygen species (ROS) and apoptosis. In addition, the activation of the ROS/JNK (c-jun NH2-terminal kinase)/p53 signaling pathway was inhibited by FM0807 in RAW 264.7 cells in vitro. Conclusion: FM0807 has anti-inflammatory activity in vitro, which suggests a potential clinical application in sepsis. The anti-inflammatory activity of FM0807 may be mediated by the ROS/JNK/p53 signaling pathway.

Mesenchymal stromal cell-derived extracellular vesicles: regenerative and immunomodulatory effects and potential applications in sepsis.

Mesenchymal stromal (stem) cells (MSCs) have multipotent differentiation capacity and exist in nearly all forms of post-natal organs and tissues. The immunosuppressive and anti-inflammatory properties of MSCs have made them an ideal candidate in the treatment of diseases, such as sepsis, in which inflammation plays a critical role. One of the key mechanisms of MSCs appears to derive from their paracrine activity. Recent studies have demonstrated that MSC-derived extracellular vesicles (MSC-EVs) are at least partially responsible for the paracrine effect. MSC-EVs transfer molecules (such as proteins/peptides, mRNA, microRNA and lipids) with immunoregulatory properties to recipient cells. MSC-EVs have been shown to mimic MSCs in alleviating sepsis and may serve as an alternative to whole cell therapy. Compared with MSCs, MSC-EVs may offer specific advantages due to lower immunogenicity and higher safety profile. The first two sections of the review discuss the preclinical and clinical findings of MSCs in sepsis. Next, we review the characteristics of EVs and MSC-EVs. Then, we summarize the mechanisms of MSC-EVs, including tissue regeneration and immunomodulation. Finally, our review presents the evidences that MSC-EVs are effective in treating models of sepsis. In conclusion, MSC-EVs may have the potential to become a novel therapeutic strategy for sepsis.

Advances in the application of exosomes in sepsis

Exosomes are of great importance in cell communication and information transmission, which have become a hotspot in recent years. Most studies have focused on the transport of microRNA (miRNA) and proteins, that mediated by exosomes, as well as exosomes as a drug delivery carrier of the feasibility. Therefore, exosomes can be an important method of treatment for systemic inflammatory diseases. This article reviews the relevant literature, mainly on the related characteristics of exosomes, its association with clinical disease, and its application in sepsis.

Evaluation of a method for murine monocyte isolation by bone marrow depletion

The study of monocyte activation and differentiation has great applications in sepsis, chronic inflammatory diseases, and cancer studies. However, despite the existence of well-established protocols for monocyte purification from human blood, the isolation of murine monocytes that can be subsequently activated has not yet been fully optimized. Here we evaluate a recently developed commercial procedure for obtaining monocytes from the bone marrow based on immunomagnetic depletion of non-monocytic cells. Moreover, we compare the advantages and disadvantages of this approach relative to other existing procedures. We found that monocytes isolates generated using this technique had equal purity to those attained via depletion from peripheral blood; however, higher yields were achieved. Furthermore, isolates from this technique have lower levels of macrophage contamination than those reported in samples generated by culturing bone marrow extracts with macrophage colony-stimulating factor (M-CSF). In addition, we demonstrate that the purified monocytes are sensitive to lipopolysaccharide (LPS)-mediated activation and, therefore, are useful for studies aimed at elucidating the molecular mechanisms involved in monocyte activation and differentiation.

Effects of S-allyl cysteine on lung and liver tissue in a rat model of lipopolysaccharide-induced sepsis.

Sepsis is characterized by a severe production of reactive oxygen species (ROS) and other radical species with consequent oxidative stress. S-allyl cysteine (SAC) is a water-soluble organosulfur component present in garlic which is a potent antioxidant and free radical scavenger. In the present study, the purpose was to explore the anti-inflammatory, antioxidant, and anti-apoptotic actions of SAC on lipopolysaccharide (LPS)-induced sepsis in rats. Thirty-two male Wistar rats were separated into 4 groups. These were control, SAC control, sepsis, and sepsis + SAC-induced groups. Sepsis was induced by administration of LPS (5mg/kg) into 2 groups. SAC (50mg/kg) was given orally to SAC control and SAC treatment groups per 12h during 2days after intraperitoneal LPS injection. Serum AST, ALT, ALP, and hsCRP levels and liver and lung MPO, NO, and DNA fragmentation levels were evaluated. In sepsis group, elevated levels of ALT, AST, ALP, and hsCRP were observed. The abnormal increases were decreased in sepsis + SAC group compared to sepsis group. In lung tissue, MPO and NO levels were increased in sepsis group compared to the control group. MPO activity and NO levels were decreased by SAC application in sepsis + SAC group compared with sepsis group. In liver tissue, DNA fragmentation was significantly higher in sepsis group than that in the control group. In contrast, a decreased level of DNA fragmentation was noted in sepsis + SAC group when compared with the sepsis group. In conclusion, SAC ameliorates LPS-induced indicators of liver damage and suppresses the discharge of NO and MPO in lung tissue via its antioxidant properties.

Ovocalyxin-36 is an effector protein modulating the production of proinflammatory mediators

Sepsis is a systemic inflammatory response syndrome during infection. Therapeutic agents are essential to protect the host from sepsis. Ovocalyxin-36 (OCX-36) is a chicken eggshell membrane protein and shares protein sequence and gene organization homology with bactericidal permeability-increasing protein (BPI), lipopolysaccharide-binding protein (LBP) and palate, lung and nasal epithelium clone (PLUNC) proteins that play a major role in innate immune protection. We recently reported that OCX-36 binds to both lipopolysaccharide (LPS) and lipoteichoic acid (LTA) (Cordeiro et al., 2013, PLoS ONE 8, e84112), which is an important activity to neutralize endotoxins and non-endotoxin pyrogens during an inflammatory response. Here we investigated the immune modulating effects of OCX-36 and enzymatically digested OCX-36 (dOCX-36) in vitro and in a mouse model of endotoxemia. OCX-36 alone dose-dependently induced both TNF-α and nitric oxide (NO) production by RAW 264.7 macrophage cells, and this immunostimulatory effect was reduced by enzymatic digestion. In the presence of LPS, dOCX-36 was more effective than intact OCX-36 at reducing LPS-induced secretion of TNF-α from RAW 264.7 cells, but did not reduce NO production. In contrast, OCX-36 increased LPS-induced NO production, both in the presence and absence of FBS, PCR array analysis confirmed that OCX-36 and dOCX-36 differentially regulated genes involved in innate immunity, and dOCX-36 down-regulated the expression of genes involved in LPS signaling and inflammatory responses. In vivo, dOCX-36 was more effective at reducing LPS-induced inflammatory symptoms and inhibiting the local production of pro-inflammatory mediators in the small intestine. These results suggest that OCX-36 and OCX-36 derived peptides may differentially modulate innate immune responses, and support our hypothesis that OCX-36 derived peptides have potential therapeutic applications in sepsis.

SB203580, a p38 Inhibitor, Improved Cardiac Function but Worsened Lung Injury and Survival During Escherichia coli Pneumonia in Mice

Supporting its therapeutic application in sepsis, p38 mitogen-activated protein kinase (MAPK) inhibition decreases cardiopulmonary injury and lethality with lipopolysaccharide challenge. However, only one preclinical study has reported the survival effects of a p38 inhibitor (SB203580, 100 mg/kg) during infection. We therefore tested SB203580 in mice (n = 763) challenged with intratracheal Escherichia coli and treated with antibiotics and fluids. Compared with placebo, high dose SB203580 (100 mg/kg) pretreatment increased the hazards ratio of death (95% confidence interval) (3.6 [2.1, 6.1], p < 0.0001). Decreasing doses (10, 1, or 0.1 mg/kg) went from being harmful to having no significant effect (p < 0.0001 for the effect of decreasing dose). At 48 hours, but not 24 hours after E. coli, high and low dose SB203580 pretreatment decreased cardiac phosphorylated p38 MAPK levels and improved cardiac output either (p <or= 0.07). Low dose SB203580 did not alter lung neutrophils significantly but increased lung injury at 48 hours (p = 0.05). High dose decreased lung neutrophils and injury at 24 hours (p = 0.09 and 0.01, respectively) but then increased them at 48 hours (both p <or= 0.01). Lung injury was greater with high versus low dose at 48 hours (p = 0.002). Thus, SB203580 had divergent effects on cardiac and lung function in E. coli challenged mice. Furthermore, high dose worsened survival and low dose did not improve it. Altogether, these findings suggest that clearly defining the risks and benefits of p38 MAPK inhibition is important before such treatment is applied in patients with or at risk of serious infection.

Rapid three-dimensional biointerfaces for real-time immunoassay using hIL-18BPa as a model antigen

With the goal of designing a rapid and affordable system of real-time immune monitoring for future diagnostic applications in sepsis, we have developed a biointerface composed of polyethyleneimine (PEI) and carboxymethylcellulose (CMC) to provide a means of prompt and facile immunoassay. Biointerface assembly is complete within 30 min, with all preparation performed and monitored within the measurement chamber of a quartz crystal microgravimetry with dissipation (QCM-D) sensor. Optimised biointerface composition, as determined by the mass of antibody immobilised, the level of antigen detection, and the amount of non-specific binding of human serum albumin, was determined to consist of a 4.0 mg/m L CMC hydrogel layer cross-linked to a 0.5 mg/m L PEI sub-layer. Tapping mode atomic force microscopy (AFM) in liquid demonstrates highly uniform and smooth surfaces using these hydrogels. Sensitivity of the biointerface for rhIL-18BPa is 400 ng/m L, with detection of 1 μg/m L achievable following 25 surface regenerations. Performance of the biointerface is verified using surface plasmon resonance (SPR), demonstrating the ability of the biointerface to be applied across platforms.

Caspase inhibition prevents cardiac dysfunction and heart apoptosis in a rat model of sepsis.

Despite intensive therapy, severe septic shock is commonly associated with myocardial dysfunction and death in humans. No new therapies have proven efficiency against cardiovascular alterations in sepsis. Here, we addressed the question of a beneficial effect of pharmacological inhibition of caspases on myocardial dysfunction following endotoxin treatment. Hearts from rats treated with endotoxin (10 mg/kg, intravenously) were isolated 4 h posttreatment for analysis. Assessment of myocardial contractility ex vivo and detection of apoptosis were performed. Hearts from endotoxin-treated rats displayed multiple caspase activities and also typical apoptosis pattern as detected by TUNEL, DNA fragmentation assays, and cytochrome c release as compared with control rats. z-VAD.fmk (3 mg/kg, intravenously), a broad spectrum caspase inhibitor (but not the irrelevant peptide z-FA.fmk), in coinjection with endotoxin, not only reduced caspase activities and nuclear apoptosis but also completely prevented endotoxin-induced myocardial dysfunction evaluated 4 h and even 14 h after endotoxin challenge. These data indicate that caspase activation plays an important role in myocardial cell dysfunction. Moreover, these results suggest that inhibitors of caspases may have important therapeutic applications in sepsis.