. The long-term goals of the applicants laboratory continue to be the elucidation of the properties and functions of pulmonary endothelial enzymes, in vivo, under normal and toxicant-altered environments. The goals of the current application focus on the applications of these functions in the development of clinically useful tests for the early diagnosis of lung injury. The studies performed since the initial award of this grant have provided new information and insights towards these long term goals. It is proposed to investigate mechanisms of angiotensin converting enzyme (ACE)-substrate and enzyme-inhibitor interactions in rabbit models of diabetes and microembolization, aiming to examine the induction as well as reversal and prevention of microvascular injury on enzyme function (diabetes) and also in studying mechanisms of altered perfused surface area (microembolization). In humans, it is proposed to investigate mechanisms of interaction between endothelium-bound ACE and clinically useful ACE inhibitors as well as correlate these interaction with the incidence of ACE gene polymorphism in an effort to identify target organ-specific ACE inhibitors and optimum biomarker conditions. Results of the proposed studies should help clarify mechanisms of induction, prevention and diagnosis of lung vascular injury.
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