Modulation of post-irradiation changes in pulmonary vasculature

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Our project is based on the over-riding hypothesis that lungs of survivors of radiological attacks and accidents will develop injury the severity of which (a) can be predicted based upon early non-invasive tests (b) are mitigated or treated with modulators of the renin-angiotensin system (RAS) and (c) is mediated in part by cytochrome P450 enzymes (CYP 4) in pulmonary vascular smooth muscle cells. Our preliminary data support vascular dropout and early changes in pulmonary vascular reactivity in rat lungs after exposure to radiation, mitigation of pulmonary injury with modifiers of the RAS, and pulmonary vascular expression and activity of a CYP isoform which has been shown to mediate biologic effects of All in renal vessels. Thus we propose to develop a rat model of radiation-induced pulmonary injury which will allow us to develop (i) markers that predict the severity of lung injury (ii) identify patients with a high likelihood of serious injury by exposure (iii) develop dosage and schedules of drugs to mitigate these injuries (iv) identify new therapeutic targets (CYP 4) that mediate the actions of angiotensin. Our specific aims are: (1) to develop an injury model consisting of a single dose of irradiation to the whole thorax in the rat which will allow us to define spatial and temporal pulmonary derangements in lung structure and function and ,to develop non-invasive means of detecting and predicting the severity of this injury (2) to study mitigating and therapeutic effects of 3 RAS modifiers (2 of which are FDA approved) on irradiation-induced lung injury and (3) to define the role of CYP 4 in mediating radiation- and angiotensin II induced changes in vascular proliferation or alterations in pulmonary artery tone and to characterize radiation-evoked changes in the distribution and 'density of mediators of RAS including local production of angiotensinogen, renin, ACE, AT1 and AT2 receptors in the pulmonary vasculature of rats. In summary, experimental studies suggest radiation-induced lung injury can be treated. The goal of this project is to bring one or more of these experimental approaches into clinical practice.