Regulation of Inflammation in Asthma by Fas Ligand

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DESCRIPTION (provided by applicant): Airway inflammation is highly associated with asthma pathogenesis and is characterized by activated Th2 lymphocytes, eosinophils and, in some cases neutrophils. The fact that the most leukocytes express the Fas death receptor implies that this pathway should be an important endogenous means of their elimination. However, there is a paucity of data regarding FasL expression in the airway, and the extent to which FasL mechanisms regulate airway inflammation in asthma is unknown. We hypothesize that the balance of FasL and FasL decoy activity (soluble Fas isoforms and DcR3) generated in the airway will be an important determinant of the intensity and duration of an IgE-mediated inflammatory response. Pro-apoptotic FasL activity should serve to limit the inflammatory response in asthma and be important for resolution, while FasL decoys should promote inflammation in this setting and may be important during initiation. This proposal consists of four interrelated aims. The first entails the definitive characterization of the principal cell types responsible for production of FasL and FasL decoys during airway inflammation and demonstrating that they can regulate their own viability (autocrine effect), or that of relevant Fas-bearing targets (paracrine effect), via soluble ligand or decoy receptor activity. The second entails regulation of these species by cytokines in resident airway macrophages, a cell type that we have found strongly expresses FasL protein after antigen challenge in work done as part of the Pl's previous K08 project. Third, endogenous sFas isoforms will be characterized, and potential FasL:sFas and FasL:DcR3 complexes generated during peak inflammation will be characterized on a molecular level. Whilethe existence of such complexes is implied in experimental systems and by our preliminary data, their existence and relevance in vivo is not known. The major source of research materials for this proposal will be derived from a human airway model of asthma using segmental antigen challenge (SAC), with a focus on the bronchoalveolar lavage compartment. There will be a limited analysis of structural cel!s in the tissue compartment. Finally, in order to help support the hypothesis that pro-apoptotic FasL activity characterized in human airway cells is truly physiologic, we will perform challenge studies in mice under FasL neutralizing conditions.