This proposal describes a 5 year training program for the development of an academic career in pulmonary medicine. Cigarette smoke-induced emphysema (EM) is a chronic process which demonstrates features of persistent inflammation, loss of elasticity and compliance, and subsequent collapse of small airways leading to permanent airflow limitations. This pathogenic process seems highly dependent on individual inherent and acquired compositions as only 25% of cigarette smokers develop EM. In this proposal, we hypothesize that the dysfunctional biosynthesis of leukotriene B4 (LTB4) and subsequent abnormal trafficking of leukocyte subpopulations and insufficient tissue healing are pivotal events that promote cigarette smoke-induced pulmonary EM. Mechanisms of the findings from our recently published studies suggest that 1) LTB4 is an important downstream leukotriene metabolite protective against EM, 2) LTB4 deficiency creates a dysfunctional tissue healing environment by suppressing necessary fibrotic healing and induction/activation of TGF-b1. Understading the interactions between LTB4 and these tissue reponses in the pathogenesis of emphysema will lead to novel therapies in the treatment and prevention of EM. In this proposal, we will test this hypothesis by performing the following experiments: (l)(a) determine time-course, magnitude, and cellular responses in the IL-13-induced murine pulmonary emphysema with and without LTB4 deficiency, (l)(b) investigate the effects of LTB4 deficiency in the IL-13-induced trafficking of leukocyte subpopulations, fibrosis, and TGF-b1 responses;(ll)(a) determine time-course, magnitude, and cellular responses in the NON-IL-13-induced murine pulmonary emphysema with and without LTB4 deficiency, (ll)(b) investigate the effects of LTB4 deficiency in the NON-IL-13-induced trafficking of leukocyte subpopulation, fibrosis, and TGF-b1 responses;(lll)(a) investigate the patterns of LTB4 biosynthesis by comparing human subjects who developed emphysema from cigarette smoking and those who did not, (lll)(b) investigate patterns of the LTB4 biosynthetic enzymes and receptors at the levels of transcription and translation in the same subjects. By successfully completing these objectives, we will have gained significant insights into the biology of LTB4 that impacts on the development of cigarette smoke induced pulmonary emphsyema, and we hope that the understanding of this pathobiology will lead to novel thrapies in the treatment and prevention of emphysema.
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