The Renin-Angiotensin System, Inflammation and Radiation-induced Brain Injury

描述(由申请人提供)：NCI已将癌症的长期存活率确定为公共卫生重点的新领域之一；癌症治疗的后遗症尤其重要。在接受脑照射治疗后长期存活的脑肿瘤患者中，约有20%-50%会发生进行性痴呆。越来越多的脑转移患者需要接受大面积或全脑照射(WBI)治疗；每年约有200,000名癌症患者接受大面积或全脑照射(WBI)治疗，这加剧了了解并尽量减少脑照射副作用的必要性。目前，放射性脑损伤还没有成功的治疗方法，也没有已知的有效的预防策略。数据支持肾素-血管紧张素系统(RAS)在辐射引起的肾脏、肺的晚期效应中的作用；血管紧张素转换酶抑制剂(ACEI)和血管紧张素II(Ang II)受体拮抗剂(ATRA)都已被证明有效。然而，涉及的致病机制(S)仍不清楚。最近的研究发现，大脑中有一种功能正常的RAS，与认知、记忆、焦虑和压力有关。我们假设，WBI上调了脑内固有的RAS，导致了慢性和持续的氧化应激/炎症反应，从而导致放射性脑损伤的发生和发展，包括认知障碍。为了验证这一假设，我们将在体外和体内追求以下特定目标：在目标1和目标2中，我们将测试这样一个假设，即在正常脑细胞中抑制Ang II将降低脑细胞表型和/或功能中促炎症变化的严重程度。我们将使用定义明确的原代大鼠星形胶质细胞、大鼠脑微血管内皮细胞和大鼠小胶质细胞模型。在AIMS 3和4中，我们将测试这一假设，即使用针对ACE(ACEI)或Ang II受体(AT1RA和AT2RA)的RAS阻滞剂抑制脑内固有的RAS将改善体内放射性脑损伤的发展和进展。大鼠将接受临床上相关的WBI分级疗程，并将确定RAS和促炎介质成分的急性(特定目标3)和慢性(特定目标4)变化，以及认知功能的慢性变化。血管紧张素转换酶II阻滞剂在调节放射性脑损伤中的介入作用的确立将导致这些发现迅速转化为临床，有望增加接受大范围或WBI治疗的癌症患者的治疗窗口，并改善他们的生活质量。

DESCRIPTION (provided by applicant): The NCI has identified long-term survival from cancer as one of the new areas of public health emphasis; the late effects of cancer treatments are of particular importance. Progressive dementia occurs in some 20-50% of brain tumor patients who are long-term survivors after treatment with brain irradiation. The need to both understand and minimize the side effects of brain irradiation is exacerbated by the ever- increasing number of patients with brain metastases that require treatment with large field or whole brain irradiation (WBI); some 200,000 cancer patients/year receive large field or WBI. At the present time, there are no successful treatments for radiation-induced brain injury, nor are there any known effective preventive strategies. Data support a role for the renin-angiotensin system (RAS) in radiation-induced late effects in kidney, lung; both angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II (Ang II) receptor antagonists (ATRA) have proved effective. However, the pathogenic mechanism(s) involved remains unknown. Recent studies have identified a functioning RAS in the brain that is involved in cognition, memory, anxiety and stress. We hypothesize that WBI upregulated the intrinsic brain RAS, leading to a chronic and persistent oxidative stress/inflammatory response that results in the development and progression of radiation-induced brain injury, including cognitive impairment. To test this hypothesis we will pursue the following in vitro and in vivo Specific Aims: In Aims 1 and 2 we will test the hypothesis that inhibiting Ang II in normal brain cells will reduce the severity of pro-inflammatory changes in brain cell phenotype and/or function. We will use well-defined models of primary rat astrocytes, rat brain microvascular endothelial cells and rat microglia. In aims 3 and 4 we will test the hypothesis that inhibiting the intrinsic brain RAS using RAS blockers targeted at either ACE (ACEI), or the Ang II receptors (AT1RA and AT2RA) will ameliorate the development and progression of radiation-induced brain injury in vivo. Rats will receive a clinically relevant fractionated course of WBI, and acute (Specific Aim 3) and chronic (Specific Aim 4) changes in components of the RAS and pro-inflammatory mediators will be determined, as well as chronic changes in cognitive function. The establishment of an interventional role for Ang II blockers in modulating radiation-induced brain injury should lead to the rapid translation of these findings to the clinic, with the promise of increasing the therapeutic window for cancer patients receiving large field or WBI as well as improving their quality of life.