The inability of present therapies to mitigate the devastating effects of sepsis and multiple organ failure in the critically ill patient suggests that more knowledge of the pathophysiology of sepsis is needed if we are to develop newer, more effective interventions. In this respect, we have learned from experimental studies using a model of polymicrobial sepsis that the otherwise normal regulatory cellular suicide response, referred to as apoptosis (Ao) or programmed cell death, appears to have pathological consequences on the septic animal's immune system when Ao is increased. By taking a multi focal approach, we have found that the effect of sepsis on a given immune cell populations' Ao response differs not only with respect to the cell type [i.e., B- or T-lymphocytes, macrophages or granulocytes (PMN)] but also with respect to their site of tissue origin and their maturational (immature/mature, naive/activated) status. Furthermore, it appears that different mediators (e.g., TNF, glucocorticoids, Fas ligand [FasL], caspases, nitric oxide [NO]) are involved in the induction of Ao in these cell populations. The pathologic significance of these altered apoptotic responses are demonstrated by our findings (in mice deficient in pro-Ao gene, FasL) as well as others (in mice over-expressing the anti-Ao Bcl-2 gene) showing that suppression of Ao in septic mice provides a survival advantage. With these data in mind we put forward the following hypothesis; that the altered apoptotic response elicited by septic stimuli, reflects a divergent pathological process that contributes to immune cell dysregulation which plays a role in inducing organ damage and the animals eventual mortality. To examine this hypothesis, we have established the following aims: 1. We will determine which specific cell/tissue (immune: lymphoid and/or phagocyte; lung; liver; intestine) populations serve as targets of FasL in septic mice, delineate how the induction of Ao is mediated (Ao gene/protein/functional change) an which cells (T-/ B-cell, macrophage and/or granulocyte) act as affecters in response to septic insult. This will be done by the judicious use of knockout mice or targeted pharmacological cell deletion studies. 2. As many of the lymphoid/macrophage populations in the septic mouse exhibit the delayed development of Ao, we will also examine the receptor mediated/signal transduction events which control this. Their actual contribution to sepsis induced Ao in mice will be ascertained by the use of specific inhibitors. 3. We will also determine if the in vivo post-treatment of mice with a FasL antagonist, a TNF antagon-ist, a steroid receptor antagonist, an inducible NO synthase (iNOS) antagonist or inhibition of Fas activated cas-pases, has comparable effects on Ao and in over-all survival of animals to that seen in FasL deficient mice. Such data will provide not only new insight into the pathobiology of sepsis, but also lead to better therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM053209-06
Application #
2903194
Study Section
Special Emphasis Panel (ZRG1-SSS-W (19))
Project Start
1995-07-01
Project End
2004-06-30
Budget Start
1999-09-30
Budget End
2000-06-30
Support Year
6
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Rhode Island Hospital (Providence, RI)
Department
Type
DUNS #
161202122
City
Providence
State
RI
Country
United States
Zip Code
02903
Wang, Fei; Huang, Xin; Chung, Chun-Shiang et al. (2016) Contribution of programmed cell death receptor (PD)-1 to Kupffer cell dysfunction in murine polymicrobial sepsis. Am J Physiol Gastrointest Liver Physiol 311:G237-45
Cheng, Tingting; Bai, Jianwen; Chung, Chun-Shiang et al. (2016) Enhanced Innate Inflammation Induced by Anti-BTLA Antibody in Dual Insult Model of Hemorrhagic Shock/Sepsis. Shock 45:40-9
Hutchins, Noelle A; Chung, Chun-Shiang; Borgerding, Joshua N et al. (2013) Kupffer cells protect liver sinusoidal endothelial cells from Fas-dependent apoptosis in sepsis by down-regulating gp130. Am J Pathol 182:742-54
Heffernan, Daithi S; Monaghan, Sean F; Thakkar, Rajan K et al. (2013) Inflammatory mechanisms in sepsis: elevated invariant natural killer T-cell numbers in mouse and their modulatory effect on macrophage function. Shock 40:122-8
Shubin, Nicholas J; Monaghan, Sean F; Heffernan, Daithi S et al. (2013) B and T lymphocyte attenuator expression on CD4+ T-cells associates with sepsis and subsequent infections in ICU patients. Crit Care 17:R276
Hutchins, Noelle A; Wang, Fei; Wang, Yvonne et al. (2013) Kupffer cells potentiate liver sinusoidal endothelial cell injury in sepsis by ligating programmed cell death ligand-1. J Leukoc Biol 94:963-70
Shubin, Nicholas J; Chung, Chun S; Heffernan, Daithi S et al. (2012) BTLA expression contributes to septic morbidity and mortality by inducing innate inflammatory cell dysfunction. J Leukoc Biol 92:593-603
Shubin, Nicholas J; Monaghan, Sean F; Ayala, Alfred (2011) Anti-inflammatory mechanisms of sepsis. Contrib Microbiol 17:108-24
McNeal, Sam I; LeGolvan, Mark P; Chung, Chun-Shiang et al. (2011) The dual functions of receptor interacting protein 1 in fas-induced hepatocyte death during sepsis. Shock 35:499-505
Guignant, Caroline; Lepape, Alain; Huang, Xin et al. (2011) Programmed death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunctions in septic shock patients. Crit Care 15:R99

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