The purpose of this project is to identify cellular and molecular mechanisms of lung injury induced by thoracic irradiation or by the alkaloid monocrotaline in rats, and to develop clinically relevant strategies of intervention. The investigation of mechanisms emphasizes the role of vascular damage in the pathogenesis of lung injury, evaluating endothelial cell responses to insult in vivo and in vitro. The project will test the hypothesis that four growth factors (basic fibroblast growth factor, hepatocyte growth factor, transforming growth factor beta, and endothelin-l) and two inflammatory mediators (leukotriene B4 and platelet- activating factor) are involved in the development of lung injury. Growth factor mRNA and product in lung will be demonstrated by Northern and Western analysis. Immunolocalization studies will be performed in situ for those factors whose Western analyses are promising. Within-animal correlations will be made between these growth factors/inflammatory mediators and four markers of pulmonary endothelial function: angiotensin converting enzyme (ACE) activity, plasminogen activator activity, and prostacyclin and thromboxane production. These in turn will be correlated with pulmonary fibrosis (hydroxyproline content), and with organ function, as assessed by pulmonary arterial perfusion scans and high resolution computed tomography. Quantitative light and electron microscopy of the lung also will be performed. The hypothesis that paracrine interactions exist among irradiated pulmonary microvascular endothelial cells, vascular smooth muscle cells, and lung fibroblasts with respect to the release of mitogens, chemotaxins, and mediators of extracellular matrix metabolism will be tested for all pairs of effector-target cell in vitro. Neutralizing antibodies will be employed to identify active agents in vitro, from among the 4 growth factors to be studied. Interest in modifiers of lung injury currently is focused on the ACE inhibitor captopril, a common antihypertensive agent. We found that captopril ameliorates radiation-induced pulmonary endothelial dysfunction and pulmonary fibrosis in rats. The present project will test the hypothesis that this salutary effect of captopril is due in part to antagonism of the above growth factors and inflammatory mediators. Radiation pneumotoxicity is a treatment-limiting factor to the oncologist, in part because its pathogenesis is unclear, and because it is refractive to management. This project addresses these problems, as captopril approaches clinical trial in radio therapy patients.
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