The objective of this project is to identify mechanisms and modifiers of pulmonary injury induced by thoracic irradiation or by the pyrrolizidine alkaloid monocrotaline damage in the pathogenesis of lung injury, and includes the ability to monitor endothelial cell reactions both in vivo and in vitro. The differential cytology of the lung at various times after injury will be determined by quantitative light and electron microscopy, and by flow cytometry. These morphologic data will be correlated with four markers of pulmonary endothelial function: angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane production. Endothelial structure and function, in turn, will be correlated with pulmonary fibrosis (lung hydroxyproline content) and with organ function (pulmonary arterial perfusion scans). The in vitro studies will evaluate the effect of injury on endothelial cell function (PLA activity and PGI2 production), and cell survival (colony formation and 51Cr-release). This project also will expand our observation that ACE inhibitors, of which Captopril is the prototype, ameliorate pulmonary endothelial dysfunction and lung fibrosis in rats sacrificed 2 months after single doses of 60Co gamma rays to the right hemithorax. The ability of Captopril to modify radiation pneumotoxicity will be determined in rats sacrificed up to one year after single-dose in endothelial cells irradiated in vitro. The timing of Captopril administration will be manipulated in irradiated rats to determine whether the drug is effective if started after pneumonitis has developed, and whether lung injury is precipitated upon drug withdrawal. Other potential modifiers to be studied include the ACE inhibitor cilazopril, the vasodilator pentoxifylline and the elastase inhibitor SC39026, alone or in injury, particularly the role of endothelial damage therein, and may identify clinically relevant strategies of intervention. Radiation pneumotoxicity is a treatment- limiting factor to the oncologist, in part because its pathogenesis is unclear and it is refractive to management. The present project addresses these problems, and should within two years provide an experimental basis to determine whether Captopril merits clinical trial as a modifier of radiation-induced lung injury.
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