Role of Nitric Oxide in Radiation-Induced Lung Injury

描述（由申请人提供）：这个指导性的职业发展计划将帮助P.I.在中断3年后，她将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好准备。该计划包括通过指导研究和教育活动进行肺毒性、炎症和药物输送方面的培训。这些经验将使P.I.以实现她成为独立调查员的总体目标。该研究的总体目标是阐明介导肺部疾病的炎症机制，特别强调活性氮物质（RONS）在疾病发病机制中的作用。尽管RONS已被证明在急性肺损伤和疾病中起关键作用，但其在肺炎和随之发生的纤维化中的作用尚不清楚，并且代表了研究的焦点。为了诱导肺炎，将使用辐射诱导的肺损伤的小鼠模型。该研究计划将测试以下假设：在辐射暴露后立即抑制RONS的产生，同时在辐射诱导的损伤的早期潜伏期期间不减少急性损伤，将显著减轻肺炎和随后的纤维化。对于这些研究，将使用1400 W，一种高度特异性的诱导型一氧化氮合酶（iNOS）抑制剂，此前已证明其可有效改善啮齿动物模型中的急性肺损伤。在目标1中，将评估通过Alzet微渗透泵给予1400 W在减轻辐射诱导的iNOS激活和RONS生成方面的疗效。将测量急性肺损伤和氧化/亚硝化应激的标志物。目标2将侧重于评估1400 W在减少继发性肺炎和纤维化方面的有效性。在目标3中，我们将优化一种新的纳米凝胶微粒系统，以选择性地将1400 W输送到辐射暴露后小鼠的肺血管室。这些研究的结果将提供关于RONS在辐射诱导的肺损伤中的作用的重要机制信息，并可能提供关于减轻肺肺炎和纤维化的新型有效治疗方案的线索。 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。识别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。 (End摘要）

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)