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中起核心作用，包括调节气道张力，血管舒张，炎症和肺形态发生。一氧化氮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。在炎症期间，NO的产生通过上调白细胞和上皮细胞中诱导型一氧化氮合酶（iNOS）的表达而增加。同时，产生氧化酶的活性增加，导致生物活性NO的病理转化为氧化活性氮。先前的工作已经确定抑制iNOS作为几种呼吸系统疾病治疗的潜在靶点，但临床干预尚未成功。我们认为iNOS抑制剂的失败是由于它们对具有保护和稳态作用的NO信号的抑制。我们假设去除较高的氧化态氮将减轻炎症并促进肺损伤的适当解决。本研究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。为了清除氧化活性氮，维生素E将通过膳食补充给药。维生素E，特别是γ -生育酚异构体，已被证明能优先清除较高的氧化物。之前我们已经研究了通过富含生育酚的饮食清除活性氧和活性氮的效果。结果显示，在博来霉素介导的损伤后，NO代谢物水平正常化，炎症减轻。本提案的第一个目的是研究在博来霉素后的分解和纤维化阶段继续补充生育酚的影响。本提案的第二个目的是研究通过去除高氧化物改变博来霉素介导的损伤的机制。特别是，我对招募和常驻细胞群的不同影响感兴趣。通过将绿色荧光蛋白阳性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常驻细胞群。对其机制的识别可能会导致新的治疗靶点的发现。这项工作为今后研究其他药理学手法和损伤模型提供了基础。

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.