) Cigarette smoke (CS) is a major factor in the pathogenesis of COPD. However, only a minority of smokers get COPD and the rate of CS-induced pulmonary deterioration differs greatly amongst individuals. CS induces emphysema via altering protease/antiprotease balance in the lung. However, the mechanisms by which CS exerts its effects and the host factors that define individual susceptibility are poorly understood. Inflammation (macrophages, lymphocytes, eosinophils, neutrophils) is common in COPD. The importance of inflammation in generating COPD, the ability of inflammation to alter proteases and antiproteases and, the degree to which different types of inflammation can account for different presentations of patients with COPD have not been defined. The investigators recently established an inducible overexpression (OE) transgenic system and used this system to overexpress IL-13 and/or gamma- interferon (IFN-gamma) in the adult murine lung. Individually, both cytokines caused impressive emphysema. With IL-13 the emphysema occurred rapidly and was associated with mucus metaplasia and macrophage, lymphocyte and eosinophil rich inflammation. In the IFN-gamma mouse, the emphysema occurred slowly, was not associated with mucus metaplasia and was associated with macrophage and granulocyte rich inflammation. Mice expressing both IFN-gamma and IL-13 had a synergistic increase in emphysema. The investigators hypothesize that: 1) IL-13 and IFN-gamma alone and in combination, activate important emphysema generating pathways in the lung; 2) effects of IL-13 and/or IFN-gamma are mediated by distinct and differentiable alterations in pulmonary protease/antiprotease balance; and 3) IFN-gamma and IL-13 play an important role in the pathogenesis of CS-induced emphysema. To test this hypothesis, the investigators propose to: 1) further define the phenotype and protease/antiprotease alterations in IL-13 OE and IFN-gamma OE mice and progeny of crosses of these animals; 2) characterize the importance of IL-13/IFN-gamma-induced alterations in protease/antiprotease balance in the generation of the emphysema seen in these animals; 3) determine if IL-13 or IFN-gamma alter the production of selected target proteases and/or antiproteases in vitro; 4) determine if the emphysema generating effects of IL-13 are restricted to IL-13 or are also a property of IL-4 or other Th2 cytokines; and 5) characterize the expression and roles of IL-13 and/or IFN- gamma in murine CS-induced emphysema.
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