NO-Modified Biomolecules and Pulmonary Signaling

描述(由申请人提供)：一氧化氮(NO)在肺生理学中的核心作用因其在维持呼吸道张力、血管张力、炎症，甚至肺的生长和发育中所起的作用而突出。除了这些重要的生理作用外，NO还与许多肺部疾病有关，包括ARDS、哮喘和囊性纤维化。到目前为止，这种简单的双原子分子能够产生如此广泛的信号的分子机制尚不清楚，此外，NO代谢的中断如何在病理中发挥作用也不清楚。这一设想的假设是，NO的氧化还原能力允许它产生一系列新颖的NO修饰的生物分子，并且这些分子本身具有信号特性。此外，有人认为，肺的氧化还原状态的破坏改变了这些分子的产生，从而影响了肺信号通路。因此，这些分子的平衡产生对肺生理学至关重要，它们的破坏可能在疾病的发病机制中发挥作用。这项建议旨在研究这些已被证明在肺细胞内具有信号传递特性的NO修饰的生物分子，即S-硝基表面活性物质蛋白D(SNO-SP-D)和硝酸亚油酸(LNO-O_2)。这些分子在上皮细胞和炎性细胞中的信号特性将被检测。以前已经证明，在一种肺部疾病的模型中，NO代谢被破坏，即博莱霉素性急性肺损伤。因此，我们将研究SNO-SP-D和LNO2在本病模型中的作用。在这种疾病模型中利用亚硝硫醇代谢受损的小鼠(GSNOR-/-)将允许更详细地检查NO修饰的生物分子在肺部病理生理学中的参与。因此，该提案将研究以下三个具体目标：1)确定S亚硝化对肺细胞SP-D信号的影响；2)确定LNO_2对肺细胞信号的作用机制；3)研究NO修饰的生物分子在病理中的作用。这些目标的实现将有助于更好地理解生物分子的NO修饰如何在肺部病理生理学中发挥作用。最终，这将允许在肺内进行更有针对性的NO治疗。与公共卫生相关。肺部炎症是目前正在上升的许多疾病的核心，如哮喘和肺气肿。化学物质一氧化氮是炎症的重要组成部分，这项研究项目将研究它如何控制肺内的细胞功能。对这些过程的更好理解可能会导致炎症性肺部疾病的新的治疗方法。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE. 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.