Modulation of post-irradiation changes in pulmonary vasculature

我们的项目是基于一个重要的假设，即放射性攻击和事故幸存者的肺部将发生损伤，其严重程度（a）可以根据早期非侵入性测试预测（B），用肾素-血管紧张素系统（RAS）调节剂减轻或治疗，（c）部分由肺血管平滑肌细胞中的细胞色素P450酶（P450）介导。我们的初步数据支持血管脱落和早期变化的肺血管反应性在大鼠肺暴露于辐射后，减轻肺损伤与RAS的修饰剂，和肺血管的表达和活性的一种亚型已被证明介导的生物效应的所有在肾血管。因此 我们建议开发放射诱导的肺损伤的大鼠模型，这将允许我们开发（i）预测肺损伤严重性的标记物（ii）识别具有通过暴露而严重损伤的高可能性的患者（iii）开发减轻这些损伤的药物剂量和时间表（iv）识别介导血管紧张素作用的新的治疗靶点（VEGF 4）。我们的具体目标是：（1）开发由对大鼠的整个胸部的单剂量照射组成的损伤模型，这将允许我们定义肺结构和功能中的空间和时间肺紊乱，开发检测和预测这种损伤严重程度的非侵入性方法（2）研究3种RAS调节剂的缓解和治疗作用（其中2个是FDA批准的）对辐射诱导的肺损伤的作用，和（3）确定RAM 4在介导辐射和血管紧张素II诱导的血管增殖变化或肺动脉张力改变中的作用，并表征辐射诱发的肺损伤。 RAS介质的分布和密度的变化，包括大鼠肺血管局部产生的血管紧张素原、肾素、ACE、AT_1和AT_2受体。 总之，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带入临床实践。

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.