Apoptosis in sepsis: a new target for therapeutic exploration (original) (raw)
Related papers
Is Suppression of Apoptosis a New Therapeutic Target in Sepsis?
Anaesthesia and Intensive Care, 2013
Sepsis remains as a leading cause of death in critically ill patients. Unfortunately, there have been very few successful specific therapeutic agents that can significantly reduce the attributable mortality and morbidity of sepsis. Developing novel therapeutic strategies to improve outcomes of sepsis remains an important focus of ongoing research in the field of critical care medicine. Apoptosis has recently been identified as an important mechanism of cell death and evidence suggests that prevention of cell apoptosis can improve survival in animal models of sepsis and endotoxaemia. In this review article, we summarise the critical role of apoptosis of the immune cells in the pathophysiology of sepsis and propose that blocking cell-signaling pathways leading to apoptosis may present a promising specific therapy for sepsis. Various methods to inhibit apoptosis including the cell surface Fas receptor pathway inhibitors, caspase inhibitors, over-expression of anti-apoptotic genes and small interfering ribonucleic acid therapy are discussed.
The role and regulation of apoptosis in sepsis
Journal of Endotoxin Research, 2005
Today, sepsis continues to be a growing problem in the critically ill patient population. A number of laboratories have been interested in understanding how changes in immune cell apoptosis during sepsis appear to contribute to septic morbidity. Consistently, it has been found that immune cell apoptosis is altered in a variety of tissue sites and cell populations both in experimental animals and humans. While divergent mediators, such as steroids and TNF, contribute to some of these apoptotic changes, their effects are tissue and cell population selective. Inhibition of FasL-Fas signaling (by either FasL gene deficiency, in vivo gene silencing [siRNA] or with FasL binding protein) protects septic mice from the onset of marked apoptosis and the morbidity/mortality seen in sepsis. Further, this extrinsic apoptosis response appears to utilize aspects of the Bid-induced mitochondrial pathway. This is in keeping with the findings that pan-specific caspase inhibition or the overexpression of Bcl-2 also protect these animals from the sequellae of sepsis.
Simultaneous activation of apoptosis and inflammation in pathogenesis of septic shock: a hypothesis1
FEBS Letters, 2003
Sepsis, a widely prevalent disease with increasing morbidity and mortality, is thought to result from uncontrolled in£ammatory responses to microbial infection and/or components. However, failure of several experimental anti-in£ammatory therapies has necessitated re-evaluation of the paradigm underlying the pathogenesis of this complex disorder. Apoptotic cell death forms a second dominant feature of septic shock in patients and animal models. Anti-apoptotic strategies may protect animals from septic death. However, simultaneous occurrence of apoptosis and in£ammation is necessary for septic death. At the cellular level, apoptosis plays a central role in the development of the lymphoid system and regulation of immune responses. Immune activation renders cells refractory to apoptosis while apoptosis of activated lymphocytes is an important immunoregulatory mechanism. Factors such as complement factor 5a, caspase-1 and mitogen-activated protein kinase, which participate in apoptosis as well as pro-in£ammatory pathways, may be responsible for simultaneous activation of apoptosis and in£ammation in sepsis. Further identi¢cation of other similar biochemical events capable of co-activating in£ammation and apoptosis may provide new targets for therapy of this hitherto untreatable disease.
Simultaneous activation of apoptosis and inflammation in pathogenesis of septic shock: a hypothesis
FEBS Letters, 2003
Sepsis, a widely prevalent disease with increasing morbidity and mortality, is thought to result from uncontrolled in£ammatory responses to microbial infection and/or components. However, failure of several experimental anti-in£ammatory therapies has necessitated re-evaluation of the paradigm underlying the pathogenesis of this complex disorder. Apoptotic cell death forms a second dominant feature of septic shock in patients and animal models. Anti-apoptotic strategies may protect animals from septic death. However, simultaneous occurrence of apoptosis and in£ammation is necessary for septic death. At the cellular level, apoptosis plays a central role in the development of the lymphoid system and regulation of immune responses. Immune activation renders cells refractory to apoptosis while apoptosis of activated lymphocytes is an important immunoregulatory mechanism. Factors such as complement factor 5a, caspase-1 and mitogen-activated protein kinase, which participate in apoptosis as well as pro-in£ammatory pathways, may be responsible for simultaneous activation of apoptosis and in£ammation in sepsis. Further identi¢cation of other similar biochemical events capable of co-activating in£ammation and apoptosis may provide new targets for therapy of this hitherto untreatable disease. ß
Sepsis-induced erythrocytes apoptosis
2007
Inkubation mit Plasma von Sepsispatienten löst in Erythrozyten einen Ca2+-Einstrom und Ceramid-Bildung aus. Dies führt zur Schrumpfung der Erythrozyten, dem "Scrambling" der Membranlipide und anschließender Oberflächenexpression von Phosphatidylserin. Die Phosphatidylserin-exprimierenden Erythrozyten können an die Gefäßwände adherieren und werden wahrscheinlich aus dem Blutstrom entfernt. Die vorliegenden Ergebnisse zeigen einen neuen pathophysiologischen Mechanismus auf, der bei Sepsis zu Störung der Mikrozirkulation und zu Anämie führt.
Apoptosis, 2009
Sepsis is a major health problem and a leading cause of death worldwide. In recent years, a crescendo of attention has been directed to the mechanisms of cell death that develop during this disease, since these are viewed as important contributors to the proinflammatory and antiinflammatory responses associated with poor outcome. Here we discuss mechanisms of cell death evident severe bacterial infection and sepsis including necrosis, apoptosis, pyroptosis, and extracellular trap-associated neutrophil death, with a particular emphasis on lymphocyte apoptosis and its contribution to the immunosuppressed phenotype of late sepsis. Individual bacterial pathogens express virulence factors that modulate cell death pathways and influence the sepsis phenotype. A greater knowledge of cell death pathways in sepsis informs the potential for future therapies designed to ameliorate immune dysfunction in this syndrome.
Cancer causes increased mortality and is associated with altered apoptosis in murine sepsis
2010
Objective-While most septic patients have an underlying comorbidity, most animal models of sepsis use mice that were healthy prior to the onset of infection. Malignancy is the most common comorbidity associated with sepsis. The purpose of this study was to determine whether mice with cancer have a different response to sepsis than healthy animals. Design-Prospective, randomized controlled study. Setting-Animal laboratory in a university medical center. Subjects-C57Bl/6 mice. Interventions-Animals received a subcutaneous injection of either 250,000 cells of the transplantable pancreatic adenocarcinoma cell line Pan02 (cancer) or phosphate-buffered saline (healthy). Three weeks later, mice given Pan02 cells developed reproducible, non-metastatic tumors. Both groups of mice then underwent intratracheal injection of either Pseudomonas aeruginosa (septic) or 0.9% NaCl (sham). Animals were sacrificed 24 hours post-operatively or followed seven days for survival. Measurements and Main Results-Cancer and healthy mice appeared similar when subjected to sham operation, although cancer animals had lower levels of T and B lymphocyte apoptosis. Cancer septic mice had increased mortality compared to previously healthy septic mice subjected to the identical injury (52% vs. 28%, p=0.04). This was associated with increased bacteremia but no difference in local pulmonary infection. Cancer septic mice also had increased intestinal epithelial apoptosis. Although sepsis induced an increase in T and B lymphocyte apoptosis in all animals, cancer septic mice had decreased T and B lymphocyte apoptosis compared to previously healthy septic mice. Serum and pulmonary cytokines, lung histology, complete blood counts and intestinal proliferation were similar between cancer septic and previously healthy septic mice.
Critical Care, 2006
Introduction Apoptosis of neutrophils (polymorphonuclear neutrophils [PMNs]) may limit inflammatory injury in sepsis and acute respiratory distress syndrome (ARDS), but the relationship between the severity of sepsis and extent of PMN apoptosis and the effect of superimposed ARDS is unknown. The objective of this study was to correlate neutrophil apoptosis with the severity of sepsis and sepsis-induced ARDS. Methods A prospective cohort study was conducted in intensive care units of three tertiary hospitals in Porto Alegre, southern Brazil. Fifty-seven patients with sepsis (uncomplicated sepsis, septic shock, and sepsis-induced ARDS) and 64 controls were enrolled. Venous peripheral blood was collected from patients with sepsis within 24 hours of diagnosis. All surgical groups, including controls, had their blood drawn 24 hours after surgery. Control patients on mechanical ventilation had blood collected within 24 hours of initiation of mechanical ventilation. Healthy controls were blood donors. Neutrophils were isolated, and incubated ex vivo, and apoptosis was determined by light microscopy on cytospun preparations. The differences among groups were assessed by analysis of variance with Tukeys. Results In medical patients, the mean percentage of neutrophil apoptosis (± standard error of the mean [SEM]) was lower in sepsis-induced ARDS (28% ± 3.3%; n = 9) when compared with uncomplicated sepsis (57% ± 3.2%; n = 8; p ARDS (53% ± 3.0%; n = 11; p n = 33; p n = 12; p = 0.13). In surgical patients with sepsis, the percentage of neutrophil apoptosis was lower for all groups when compared with surgical controls (52% ± 3.6%; n = 11; p Conclusion In medical patients with sepsis, neutrophil apoptosis is inversely proportional to the severity of sepsis and thus may be a marker of the severity of sepsis in this population.
2004
A rodent model of sepsis was used to establish the relationship between caspase inhibition and inhibition of apoptotic cell death in vivo. In this model, thymocyte cell death was blocked by Bcl-2 transgene, indicating that apoptosis was predominantly dependent on the mitochondrial pathway that culminates in caspase-3 activation. Caspase inhibitors, including the selective caspase-3 inhibitor M867, were able to block apoptotic manifestations both in vitro and in vivo but with strikingly different efficacy for different cell death markers. Inhibition of DNA fragmentation required substantially higher levels of caspase-3 attenuation than that required for blockade of other apoptotic events such as spectrin proteolysis and phosphatidylserine externalization. These data indicate a direct relationship between caspase inhibition and some apoptotic manifestations but that small quantities of uninhibited caspase-3 suffice to initiate genomic DNA breakdown, presumably through the escape of catalytic quantities of caspase-activated DNase. These findings suggest that putative caspase-independent apoptosis may be overestimated in some systems since blockade of spectrin proteolysis and other cell death markers does not accurately reflect the high degrees of caspase-3 inhibition needed to prevent DNA fragmentation. Furthermore, this requirement presents substantial therapeutic challenges owing to the need for persistent and complete caspase blockade.