Dietary Scavenging of Reactive Species in Lung Injury: Role of Macrophages

描述(申请人提供)：一氧化氮在呼吸生理学中发挥核心作用，包括调节呼吸道张力、血管扩张、炎症和肺形态发生。NO产生的改变与许多呼吸系统疾病的病理有关，如哮喘、肺气肿和急性呼吸窘迫综合征。在炎症过程中，通过上调白细胞和上皮细胞中诱导型一氧化氮合酶(INOS)的表达来增加NO的产生。同时，氧化剂产生酶的活性增加，导致生物活性NO在病理上转化为氧化的活性氮物种。先前的工作已经发现抑制iNOS是几种呼吸道疾病的潜在治疗靶点，然而临床干预一直没有成功。我们认为，iNOS抑制剂的失败是由于它们抑制了NO信号转导，而NO信号转导具有保护和内环境平衡的作用。我们假设，去除较高的氮氧化物物种将减轻炎症，并促进肺损伤的适当解决。这项建议使用气管内博莱霉素来模拟肺损伤，因为它包括炎症和消退阶段。为了清除氧化的活性氮物种，维生素E将通过饮食补充来补充。维生素E，特别是γ-生育酚异构体，已被证明优先清除较高的氧化物。此前，我们已经研究了通过生育酚强化饮食清除活性氧和氮物种的效果。结果显示，博莱霉素性损伤后NO代谢产物水平恢复正常，炎症反应减轻。这项建议的第一个目的是研究在博莱霉素之后的消退和纤维化阶段继续补充生育酚的效果。这项建议的第二个目的是研究去除较高的氧化物物种改变博莱霉素介导的损伤的机制。特别是，我感兴趣的是对招募细胞和常驻细胞群体的不同影响。通过将绿色荧光蛋白阳性的骨髓细胞过继转移到野生型受体而产生的嵌合小鼠，将用于识别招募和驻留的细胞群体。对该机制的识别可能导致发现新的治疗靶点。这项工作为以后研究其他药理操作和损伤模型奠定了基础。

DESCRIPTION (provided by applicant): Nitric oxide plays a central role in respiratory physiology including regulation of airway tone, vasodilation, inflammation and lung morphogenesis. An alteration of NO production has been implicated in the pathology of numerous respiratory diseases such as asthma, emphysema and the acute respiratory distress syndrome. During inflammation, NO production is increased via upregulation of inducible nitric oxide synthase (iNOS) expression in leukocytes and epithelial cells. Simultaneous increased activity of oxidant producing enzymes, leads to pathologic conversion of bioactive NO into oxidized reactive nitrogen species. Previous work has identified inhibition of iNOS as a potential target of therapy in several respiratory pathologies, however clinical intervention has been unsuccessful. It is our contention that the failure of iNOS inhibitors is due to their inhibition o NO signaling which serves a protective and homeostatic role. We hypothesize that removal of higher oxide species of nitrogen will attenuate inflammation and facilitate proper resolution in lung injury. This proposal uses intratracheal bleomycin to model lung injury as it includes an inflammation and resolution phase. In order to scavenge oxidized reactive nitrogen species vitamin E will be administered via dietary supplementation. Vitamin E, in particular the gamma-tocopherol isoform, has been shown to preferentially scavenge higher oxides. Previously we've studied the effect of scavenging reactive oxygen and nitrogen species, via tocopherol enriched diet. Results showed normalized NO metabolite levels and reduction of inflammation following bleomycin mediated injury. The first aim of this proposal is to study the effect of continued tocopherol supplementation through the resolution and fibrosis phases following bleomycin. The second aim of this proposal is to study the mechanism by which the removal of higher oxide species alters bleomycin mediated injury. In particular, I am interested in the differential effect on the recruited and resident cell populations. Chimeric mice, created by adoptive transfer of green fluorescent protein positive bone marrow cells to wild type recipients, will serve to identif the recruited and resident cell populations. Identification of the mechanism may result in discovery of novel therapeutic targets. This work provides a basis for a career studying other pharmacologic manipulations and injury models.