Role of Nitric Oxide in Radiation-Induced Lung Injury

描述(申请人提供)：这项有指导的职业发展计划将帮助P.I.在中断3年后重新进入生物医学研究领域，并将为她进行专注于肺部疾病发病机制和治疗的独立研究做准备。该计划包括通过有指导的研究和教育活动进行肺部毒性、炎症和药物输送方面的培训。这一经历将使私家侦探实现成为独立调查员的总体目标。这项研究的总体目标是阐明介导肺部疾病的炎症机制，特别强调活性氮在疾病发病机制中的作用。虽然RONS已被证明在急性肺损伤和疾病中起关键作用，但它们在肺炎和随后的纤维化中的作用尚不清楚，这是研究的重点。为了诱发肺炎，将使用辐射诱导的肺损伤的小鼠模型。该研究计划将检验这一假设，即在辐射暴露后立即抑制RON的产生，而不是在辐射诱导损伤的早期潜伏期减少急性损伤，将显著减轻肺炎和随之而来的纤维化。在这些研究中，将使用1400W，一种高度特异的诱导型一氧化氮合酶(INOS)抑制剂，此前已被证明对改善啮齿动物模型的急性肺损伤有效。在目标1中，将评估1400W的阿尔茨海默特微渗泵在减轻辐射诱导的iNOS激活和RON产生方面的效果。将对急性肺损伤和氧化/亚硝化应激的标志物进行测量。目标2将重点评估1400W在减少继发性肺炎和纤维化方面的有效性。在目标3中，我们将优化一种新型纳米凝胶微粒系统，以选择性地将1400W辐射后输送到小鼠的肺血管间。这些研究结果将为RONS在放射性肺损伤中的作用提供重要的机制信息，并可能为减轻肺肺炎和肺纤维化的新的有效治疗方案提供线索。 相关性(见说明)：急性肺损伤引起的肺炎和纤维化是主要的健康问题。确定导致这些病理的机制和有效的治疗方案是最大限度地减少慢性肺损伤的关键。(摘要结束)

DESCRIPTION (provided by applicant): This mentored career development plan will help the P.I. re-enter the field of biomedical research after a 3- year hiatus, and will prepare her to conduct independent research focusing on pulmonary disease pathogenesis and treatment. The plan includes training in pulmonary toxicity, inflammation, and drug delivery through mentored research and educational activities. This experience will enable the P.I. to achieve her overall goal of becoming an independent investigator. The overall goal of the research is to elucidate inflammatory mechanisms mediating lung disease with a particular emphasis on the role of reactive nitrogen species (RONS) in disease pathogenesis. Although RONS have been shown to play a key role in acute lung injury and disease, their role in pneumonitis and consequent fibrosis is unknown and represents the focus of the research. To induce pneumonitis, a mouse model of radiation-induced lung injury will be used. The research plan will test the hypothesis that inhibiting production of RONS immediately following radiation exposure, while not reducing acute injury during the early latent phase of radiation induced injury, will significantly mitigate pneumonitis and consequent fibrosis. For these studies 1400W, a highly specific inhibitor of inducible nitric oxide synthase (iNOS), which has previously been shown to be effective in ameliorating acute lung injury in rodent models will be used. In aim 1, the efficacy of 1400W administered by Alzet micro-osmotic pumps in mitigating radiation induced iNOS activation and RONS generation will be assessed. Measurements will be made of markers of acute lung injury and oxidative/nitrosative stress. Aim 2 will be focused on assessing the effectiveness of 1400W in reducing consequent pneumonitis and fibrosis. In Aim 3, we will optimize a novel nanogel microparticle system to selectively deliver 1400W to the pulmonary vascular compartment of mice after radiation exposure. The results of these studies will provide important mechanistic information on the role of RONS in radiation induced lung injury and may provide clues on a novel efficacious treatment protocol for mitigating lung pneumonitis and fibrosis. RELEVANCE (See instructions): Pneumonitis and fibrosis consequent to acute lung injury are of major health concern. The identification of mechanisms leading to these pathologies and effective treatment protocols is key to minimizing chronic lung injury. (End of Abstract)