Modulation of post-irradiation changes in pulmonary vasculature

我们的项目建立在辐射攻击和事故幸存者的肺会发生损伤的压倒一切假设的基础上，损伤的严重性(A)可以基于早期的非侵入性测试来预测，(B)肾素-血管紧张素系统(RAS)的调节剂减轻或治疗，以及(C)部分由肺血管平滑肌细胞中的细胞色素P450酶(CyP4)介导。我们的初步数据支持辐射后大鼠肺血管丢失和肺血管反应性的早期变化，RAS的修饰剂减轻肺损伤，以及肺血管中CYP亚型的表达和活性，已被证明介导了肾血管中ALL的生物效应。因此， 我们建议建立一种放射性肺损伤的大鼠模型，这将使我们能够开发(I)预测肺损伤的严重程度的标记物(Ii)识别因暴露而严重损伤的高可能性患者(Iii)开发减轻这些损伤的药物的剂量和时间表(Iv)确定新的治疗靶点(CYP 4)，以介导血管紧张素的作用。我们的具体目标是：(1)建立一种单次照射大鼠全胸的损伤模型，使我们能够确定肺结构和功能在空间和时间上的紊乱，并发展非侵入性手段来检测和预测这种损伤的严重程度；(2)研究3种RAS修饰剂(其中2种是FDA批准的)对放射性肺损伤的缓解和治疗作用；(3)确定CyP4在介导辐射和血管紧张素II诱导的血管增殖或肺动脉张力变化中的作用，并表征辐射诱导的肺血管张力变化 血管紧张素原、肾素、血管紧张素转换酶1和血管紧张素转换酶2受体在大鼠肺血管内的分布和密度变化。 总而言之，实验研究表明，放射性肺损伤是可以治疗的。该项目的目标是将这些实验方法中的一种或多种应用于临床实践。

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.