Eosinophils are the most abundant and injurious of the effector cells of asthma where there is evidence for their enhanced differentiation and release from bone marrow; recruitment, activation and prolonged survival. It is hypothesized that eosinophil longevity in the asthmatic airway contributes to eosinophil accumulation and capacity to damage the asthmatic airway via production of inflammatory mediators, cytokines, reactive oxygen species, and most importantly, the eosinophilic cationic proteins which lead to the airway hyperreactivity Resolution of asthmatic eosinophilic inflammation requires eosinophil apoptosis and removal, and it is the objective of this proposal to determine the mechanisms by which apoptosis occurs. Apoptotic eosinophils are seen more often in the asthmatic airway lumen than tissue, and it is the objective of this proposal to determine the mechanisms by which apoptosis occurs. Apoptotic eosinophils are seen more often in the asthmatic airway lumen than tissue, and it is hypothesized that this can be explained by three factors: loss of pro- survival cytokine stimulation in the airway lumen; the presence of pro- apoptotic factors at this site; and inefficient clearance by phagocytes in the airway lumen, relative to tissue. While the importance of pro- survival signaling by the HSFs has been investigated, little is known of integrated signaling from the interplay or """"""""mix"""""""" of pro-survival (HSFs, integrins, chemotactic factors) and pro-apoptotic signaling (Fas, TNF- alpha, oxidant generation, corticosteroids), which are expected to occur in vivo. From preliminary data, it is hypothesized that constitutive apoptosis is driven by oxidant production from mitochondria, and that responses to """"""""mixed"""""""" signaling are determined by oxidant generation, mitochondrial protection by MnSOD, and autocrine production of survival factors. Furthermore, while signaling via NFkappaB, Akt and ERK are thought to be redundant in HSF pro-survival signaling, it is hypothesized that these pathways become critical for survival during """"""""mixed"""""""" signaling . These pathways are also expected to determine eosinophil response during corticosteroid treatment where inhibition of NFkappaB results in loss of MnSOD protection of mitochondria, apoptosis and rapid secondary cytolysis (with release of cationic proteins to the tissues). Conversely, pro-apoptosis and rapid secondary cytolysis (with release of cationic proteins to the tissues). Conversely, pro-survival signaling leads to MnSOD expression and mitochondrial protection which results in eosinophil insensitivity to corticosteroids. These hypothesis will be investigated both in vitro in isolated eosinophils, and in vivo using the murine allergen challenge model of airway hyperreactivity and in human allergic asthma. Findings are expected to broaden our understanding of eosinophil longevity and offer new insights into potential therapeutic targets.
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