Mechanisms of Resolution in Experimental Asthma

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DESCRIPTION (provided by applicant): Asthma is a serious disease that can have debilitating and sometimes fatal effects on its sufferers. The failure of asthmatics to resolve inflammation in their airways after exacerbations remains one of the most problematic features of the disease. This persistent inflammation is believed to be a major contributor to the frequency and severity of asthma as well as many characteristics of asthma such as airway remodeling, smooth muscle hypertrophy, and airway hyperreactivity. However, the normal mechanisms by which Th2-mediated inflammation resolves are largely unknown. We have been investigating the role of Fas (CD95), a cell surface death receptor, in the resolution of airway inflammation. Even though Th2 cells have been found to be resistant to Fas-mediated apoptosis in vitro, our preliminary data demonstrate that Fas-deficiency leads to a 4-7 day delay in resolution of Th2-mediated murine airway inflammation. Fas-deficient T cells are sufficient to induce this persistence of inflammation in an adoptive transfer model. Importantly, while mice that receive wild type T cells resolve acute allergen-induced inflammation around 2 weeks after the last challenge, mice that receive Fas-deficient T cells develop a persistent inflammatory phase that lasts at least 4 weeks longer. This chronic phase occurs in the absence of additional antigen challenges, and includes many pathological features of human asthma including continued inflammatory cells in the airways, dramatic mucus production, and airway hyperreactivity. Thus, our murine model of chronic Th2-mediated airway inflammation is unusual since it develops due to a failure to resolve an acute response, not due to chronic allergen challenges or genetic manipulation. We posit that this persistent inflammation is a model for the chronic inflammation found in mild to moderate asthmatics during symptom-free periods between exacerbations and that elucidating the mechanisms involved of this persistent inflammation will provide fundamental knowledge about resolution of lung inflammation in asthmatic patients. The overall hypothesis of this proposal is that the prolonged inflammation characteristic of asthmatic patients may be due directly or indirectly to defects in Fas-mediated signals to Th2 cells during the resolution of exacerbations. The goal of this application is to elucidate the mechanisms involved in the development and persistence of inflammation in our murine model.