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

描述（由申请人提供）：一氧化氮在呼吸生理学中起核心作用，包括气道张力、血管舒张、炎症和肺形态发生的调节。NO产生的改变与许多呼吸道疾病如哮喘、肺气肿和急性呼吸窘迫综合征的病理学有关。在炎症过程中，NO的产生通过白细胞和上皮细胞中诱导型一氧化氮合酶（iNOS）表达的上调而增加。同时增加的氧化剂产生酶的活性，导致生物活性NO病理转化为氧化的活性氮物质。以前的工作已经确定了iNOS的抑制作为一个潜在的目标，在几个呼吸道疾病的治疗，但临床干预一直是不成功的。我们的论点是，iNOS抑制剂的失败是由于它们抑制NO信号传导，这起到保护和稳态作用。我们假设，去除氮的高氧化物将减轻炎症，促进肺损伤的适当解决。该提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。为了抑制氧化活性氮，将通过膳食补充剂给予维生素E。维生素E，特别是γ-生育酚同种型，已被证明优先吸收较高的氧化物。以前，我们已经研究了通过富含生育酚的饮食清除活性氧和氮的效果。结果显示，在博来霉素介导的损伤后，NO代谢物水平正常化并且炎症减少。本提案的第一个目的是研究博来霉素治疗后在消退期和纤维化期持续补充生育酚的效果。该提议的第二个目的是研究去除较高氧化物物种改变博来霉素介导的损伤的机制。特别是，我感兴趣的是对招募和居民细胞群的差异效应。通过将绿色荧光蛋白阳性骨髓细胞过继转移至野生型受体而产生的嵌合小鼠将用于鉴定募集的和驻留的细胞群体。该机制的鉴定可能导致发现新的治疗靶点。这项工作为研究其他药理学操作和损伤模型的职业生涯提供了基础。

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.