Prevention of Lymphocyte Apoptosis—A Potential Treatment of Sepsis?

Abstract

Sepsis is the leading cause of death in surgical intensive care units and is a major cause of morbidity and mortality in neonatal and medical intensive care units. The Centers for Disease Control and Prevention estimates that, in the United States alone, approximately 500,000 people develop sepsis and 175,000 people die each year. Sepsis is a growing problem; its incidence has tripled from 1972 to 1992. Recently, apoptosis has been identified as an important mechanism of cell death in animal models of sepsis and endotoxemia. During sepsis, there is extensive apoptotic death of lymphocytes and gastrointestinal epithelial cells. The extensive apoptotic death of lymphocytes is likely an important cause of the profound immunosuppression that is a hallmark of patients with sepsis. The apoptosis of gastrointestinal epithelial cells may compromise the integrity of the bowel wall, resulting in translocation of bacteria or endotoxins into the systemic circulation. The potential importance of apoptosis in the pathophysiology of sepsis is illustrated by results from animal models that demonstrate that blocking lymphocyte apoptosis improves survival in sepsis. A variety of strategies to inhibit apoptosis may ultimately provide an effective therapy for this highly lethal disorder.

Monitoring Immune Dysfunctions in the Septic Patient: A New Skin for the Old Ceremony

“…This deleterious role of apoptosis has been largely demonstrated in numerous murine experiments in which its prevention improved the likelihood of survival. Several inhibitory strategies have been applied, which may point to novel therapeutic approaches in the clinic: caspase inhibitors, antiretroviral protease inhibitors, Fas targeting siRNA, Bcl-2 overexpression, CD95 inhibition (13,138,156,157). Most importantly, the degree of apoptosis of circulating lymphocytes correlates with sepsis severity and predicts fatal outcome, suggesting the importance of its measurement as a prognostic biomarker to help in stratifying patients.…”

“…Finally, strategies designed at blocking apoptosis, including caspase inhibitors, overexpression of Bcl-2, and inhibition of Fas/FasL signaling, have demonstrated survival improvement in animal models of sepsis as well (13,138,156,157). That said, no therapeutic strategy is sufficiently developed for clinical use.…”

Renal Hemodynamic, Inflammatory, and Apoptotic Responses to Lipopolysaccharide in HO-1−/− Mice

“…Because apoptosis of lymphocytes is well recognized in human and experimental sepsis, 5,[25][26][27][28] we evaluated the histological appearance of the spleen and thymus. After LPS, HO-1 Ϫ/Ϫ mice but not HO-1 ϩ/ϩ mice exhibited marked evidence of apoptosis, the latter not observed in the spleen of vehicle-treated HO-1 ϩ/ϩ and HO-1 Ϫ/Ϫ mice (data not shown).…”

NK but Not CD1-Restricted NKT Cells Facilitate Systemic Inflammation during Polymicrobial Intra-Abdominal Sepsis

“…However, the contributions of lymphoid populations to the pathogenesis of sepsis are less well characterized. Several studies indicate that T lymphocyte dysfunction contributes to a state of immunosuppression during the later stages of sepsis, which may predispose the septic host to further infectious complications (5)(6)(7). However, the contributions of lymphoid cells to the inflammatory component of septic shock have not been determined.…”