The central role that Nitric Oxide (NO) plays within pulmonary physiology is highlighted by the number of functions in which it plays a role including the maintenance of airway tone, blood vessel tone, inflammation, and even lung growth and development. In addition to these important physiological roles NO has also been implicated in a number of pulmonary diseases including ARDS, Asthma, and cystic fibrosis. As yet the molecular mechanisms by which this simple diatomic molecule can produce such a wide range of signals is unclear, furthermore, it is unclear how disruption of NO metabolism may play a role in pathology. It is the hypothesis of this proposal that the redox capabilities of NO allow it to generate a series of novel NO-modified biomolecules and that these molecules themselves have signaling properties. Furthermore, it is contended that disruption of the redox status of the lung alters the production of these molecules such that pulmonary signaling pathways are affected. Therefore the balance of the production of these molecules is critical to pulmonary physiology and their disruption could play a role in the pathogenesis of disease. This proposal seeks to examine such NO- modified biomolecules which have been demonstrated to possess signaling properties within pulmonary cells, namely S-nitrosylated Surfactant Protein D (SNO-SP-D) and nitrolinoleic acid (LNO2). The signaling properties of these molecules in epithelial and inflammatory cells will be examined. Previously it has been shown that NO metabolism is disrupted in a model of pulmonary disease, namely bleomycin-induced acute lung injury. Therefore the involvement of SNO-SP-D and LNO2 within this disease models will be examined. Utilization of mice in which nitrosothiol metabolism is impaired (GSNOR-/-) within this disease model will allow for more detailed examination of the involvement of NO-modified biomolecules in pulmonary pathophysiology. The proposal will therefore examine the following three specific aims: 1) To determine the effects of S-nitrosylation on SP-D signaling in pulmonary cells; 2) To determine the mechanisms of LNO2 on pulmonary cell signaling; 3) To examine the role of NO-modified biomolecules in pathology. Achievement of these aims will allow for a better understanding of how NO-modification of biomolecules plays a role in pulmonary pathophysiology. Ultimately this will allow for more focused NO-based therapeutics within the lung.
. Pulmonary inflammation lies at the heart of many diseases that are currently on the rise such as asthma and emphysema. The chemical nitric oxide is an important part of inflammation and this research project will investigate how it controls cellular function within the lung. A greater understanding of these processes may lead to novel therapeutic approaches for inflammatory lung diseases. ? ? ?
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