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.