Mechanism of hypoxia mediated radiation lung injury

缺氧介导的放射性肺损伤的机制

• 批准号: 6927207
• 负责人: ZELJKO VUJASKOVIC
• 金额: $ 27.41万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6927207
• 关键词: biomimetics; blood vessels; cardiovascular injury; disease /disorder prevention /control; electron spin resonance spectroscopy; enzyme activity; free radical oxygen; gadolinium; immunocytochemistry; laboratory rat; leukocyte activation /transformation; lung injury; lung ischemia /hypoxia; macrophage; metalloporphyrins; neoplasm /cancer radiation therapy; nonhuman therapy evaluation; oxygen consumption; pathologic process; pulmonary circulation; radiobiology; superoxide dismutase; therapy adverse effect; transforming growth factors; vascular endothelial growth factors

DESCRIPTION (provided by applicant): The risk of unacceptable radiation (RT)-induced lung injury remains a significant limiting factor in the current treatment of the tumors involving the thoracic region. Despite advances in normal tissue radiobiology demonstrating that ionizing radiation triggers a cascade of genetic and molecular events, which lead to pulmonary injury, it is still unclear how a prolonged response to injury can be sustained for months to years after irradiation has ended. This deficiency in understanding of the mechanisms of RT-induced lung injury has hindered the development of appropriate interventional approaches to prevent this serious problem. The current proposal is based on our recent finding implicating hypoxia as an important contributing factor in the development of RT-induced pulmonary injury. We believe that hypoxia results from two factors: 1) increased oxygen consumption by activated macrophages with associated production of reactive oxygen species (ROS) and cytokines, and 2) decreased oxygen delivery to tissue due to vascular damage causing reduced perfusion. We hypothesize that hypoxia mediates a cycle of continuous, macrophage-associated production of ROS and expression/activation of profibroqenic and proanqioqenic cytokines. This process leads to l disre.qulation of angiogenesis, endothelial cell death, and collagen deposition which result in sustained hypoxia that I_erpetuates further pulmonary tissue damage and fibrosis, The goal of this study is to determine the I temporal onset of hypoxia after lung irradiation, and to define how hypoxia relates to macrophage activity (the production of ROS and cytokines) and vascular damage at different time points after irradiation. Lung hypoxia will be determined using the EF5 hypoxia marker. Macrophage activation will be assessed by immunohistochemistry. ROS will be detected using electron spin resonance (ESR) spectroscopy and spin trapping. A radionuclide perfusion assay will be used to assess pulmonary perfusion. After characterizing the relationship between hypoxia, macrophage activation and vascular damage following RT we will attempt to disrupt this injury cycle in two ways. First, ROS will be targeted directly with superoxide dismutase (SOD) mimetics. Second, ROS mediated injury will be targeted indirectly by inhibiting macrophage activity with gadolinium chloride (GdCI3). If successful, this project may lead directly to the development of clinically applicable strategies to reduce the risk of RT-induced lung injury in an attempt to permit delivery of higher doses of radiation to thoracic tumors without increasing the risk of pulmonary complications.

描述（由申请人提供）：不可接受的辐射（RT）引起的肺损伤的风险仍然是当前涉及胸部区域的肿瘤治疗中的一个重要限制因素。尽管正常组织放射生物学的进展表明，电离辐射会引发一系列遗传和分子事件，从而导致肺损伤，但仍不清楚在辐射结束后，对损伤的长期反应如何能够持续数月至数年。对放疗引起的肺损伤机制的了解不足，阻碍了预防这一严重问题的适当介入方法的开发。目前的提议是基于我们最近的发现，即缺氧是 RT 引起的肺损伤发生的一个重要因素。我们认为缺氧是由两个因素造成的：1）活化的巨噬细胞耗氧量增加，并产生活性氧（ROS）和细胞因子，2）由于血管损伤导致灌注减少，导致组织的氧输送减少。我们假设缺氧介导了巨噬细胞相关的 ROS 持续产生以及促纤维细胞因子和促细胞因子表达/激活的循环。这一过程导致血管生成失调、内皮细胞死亡和胶原沉积，从而导致持续缺氧，从而进一步导致肺组织损伤和纤维化。本研究的目的是确定肺照射后缺氧的时间开始，并确定不同时间缺氧与巨噬细胞活性（ROS和细胞因子的产生）和血管损伤的关系 照射后的点。将使用 EF5 缺氧标记物确定肺缺氧。将通过免疫组织化学评估巨噬细胞活化。将使用电子自旋共振 (ESR) 光谱和自旋捕获来检测 ROS。放射性核素灌注测定将用于评估肺灌注。在描述了放疗后缺氧、巨噬细胞活化和血管损伤之间的关系后，我们将尝试以两种方式破坏这种损伤循环。首先，超氧化物歧化酶 (SOD) 模拟物将直接靶向 ROS。其次，通过用氯化钆（GdCI 3 ）抑制巨噬细胞活性来间接靶向ROS介导的损伤。如果成功，该项目可能会直接导致临床适用策略的开发，以降低放疗引起的肺损伤的风险，以尝试在不增加肺部并发症风险的情况下向胸部肿瘤提供更高剂量的辐射。