Apoptosis, or programmed cell death, is recognized to play a critical role in the regulation of inflammation, tissue injury, and the host immune response. Recent studies have identified Fas (CD95) as an important cell surface receptor mediating the induction of apoptosis in a wide variety of tissues, including the hematopoietic and immune systems. In contrast to Fas, the expression of its natural ligand, FasL, is relatively restricted. The vast majority of research conducted to date has focused on the Fas/FasL system in lymphocytes and its critical role in lymphoid development. In contrast, relatively little is known regarding the Fas/FasL system in phagocytes and its role in innate immunity and the pathogenesis of acute inflammation and tissue injury. Whereas lymphocytes must be activated to express significant levels of FasL, recent evidence indicates that human neutrophils and monocytes/macrophages constituitively express FasL in an intracellular form which can be mobilized and deployed on the cell surface. Furthermore, these cells can be activated to rapidly release biologically active soluble FasL (sFasL), which, in turn, induces death of heterologous cells. Thus, the Fas/FasL system represents a novel cytokine system with important implications for innate immunity and inflammation. This project will characterize the intracellular storage and functional role of phagocyte-derived FasL, including its interaction with other mediators of phagocyte cytotoxicity and its possible role as a cellular activating (rather than death-inducing) for monocytes/macrophages. The role of the Fas/FasL system in the pathogenesis of acute tissue injury associated with inflammation in vivo will be examined using a model of acute inflammatory lung injury in genetically-defined mice. Acute lung inflammation and injury will be examined in both Fas-deficient (Ipr/lpr) and FasL- deficient (gld/gld) mice, as well as in transgenic lung-epithelial-specific FADD dominant negative mice to assess the contribution of membrane receptor-mediated death pathways to acute lung inflammation. The effect of disruption of the Fas/FasL system on phagocyte survival during acute inflammation in vivo will also be assessed. The project will also investigate whether sFasL is released and functions as a death-inducing cytokine during the course of the acute respiratory distress syndrome (ARDS) in human patients. The long-term objective of this work is to understand the role of cell death in acute inflammation and associated tissue injury. The comprehensive experimental approach described here promises to yield fundamental insights into phagocyte biology, innate host defense, and the pathogenesis of tissue injury during inflammation. Such information may provide the basis for the development of novel therapeutic strategies to limit deleterious sequelae of the immune response in clinical diseases associated with phagocyte infiltration and inflammation.
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