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.
The production of the signaling molecule nitric oxide is a known mediator of inflammation and injury in a variety of lung diseases. However, inhibiting total nitric oxide production has failed to improve clinical endpoints, possibly because nitric oxide has some beneficial effects. In this proposal, we will examine with vitamin E how dietary scavenging of the more toxic compounds derived from nitric oxide reduces lung injury.