MECHANISMS OF PROGRAMED CELL DEATH IN EOSINOPHILS

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DESCRIPTION (Adapted from applicants' abstract) Airway eosinophilia is a prominent feature of the inflammation in asthma, and current evidence suggests that these cells contribute significantly to asthma pathogenesis. The focus of the PI's research experience to date has been the study of the cellular and humoral events which take place in the asthmatic airway during IgE-mediated inflammation, using the model of segmental antigen challenge in humans. The motivation for writing this application is based upon several in vivo and in vitro observations derived from these studies, namely the presence of prolonged airway eosinophilia in late phase asthmatics, and the differential viability characteristics between airway and circulating eosinophils in culture. This suggests that apoptotic pathways are suppressed/ impaired during eosinophilic inflammation. The mechanisms by which the life span of an eosinophil is regulated at the site of allergic inflammation are unclear at present. They must include factors that promote cell survival initially, and factors that trigger the programmed cell death pathway, ultimately. Eosinophils spontaneously undergo apoptosis when removed from the circulation, but will respond to specific cytokines, such as IL-5, with a marked prolongation in viability. In contrast, programmed cell death in eosinophils is accelerated by treatment with glucocorticoids, or cross linking of surface Fas-antigen which these cells have recently been found to express. The molecular mechanisms underlying Fas- and glucocorticoid-mediated killing of eosinophils, and the extent to which they are active in vivo, are unknown. Significantly, killing by glucocorticoids, but not by Fas engagement, is antagonized by IL-5 suggesting that these agents act at different levels of the cell death pathway. Certain proteins have emerged as critical regulators of apoptosis and include the pro-apoptotic Ced-3-related cysteine proteases (caspases), and anti-apoptotic factors such as Bcl-2. The applicants hypothesize that substances which accelerate eosinophil apoptosis (i.e. glucocorticoids or Fas activation), act by altering the balance or the activity of these apoptotic regulators, particularly the cysteine proteases and associated molecules. They further hypothesize that because eosinophils are exquisitely sensitive to Fas-mediated killing, this must represent a physiologic mechanism by which eosinophilia is controlled during IgE-mediated inflammation in vivo. (End of Abstract)