S-NITROSOTHIOL BREAKDOWN BY AIRWAY EPITHELIAL CELLS

一般的S-亚硝基硫醇（SNO）和一般的S-亚硝基谷胱甘肽（GSNO） 特别是-是稳定的，有效的支气管扩张剂， 调节功能，并存在于正常的人体气道中。 哮喘性支气管痉挛与反常的低气道SNO相关 水平-和无法检测的GSNO水平-尽管相对较高 呼出空气中一氧化氮（NO）的浓度和 诱导型一氧化氮合酶 这个悖论最好的解释可能是 考虑到GSNO是生物活性氮氧化物的储库， 呼吸道-就像在大脑和其他组织中一样-呼吸道的破裂 在哮喘中会加速。 在这个意义上，气道SNO催化剂可能 导致高呼出NO浓度和支气管痉挛 哮喘病人的情况 本项目将测试以下假设：1） 气道上皮细胞分解代谢SNO; 2）SNO分解代谢活性 气道上皮细胞的数量被哮喘相关的兴奋剂改变 病理生理学;和3）气道上皮细胞介导的SNO catalysis 抑制气道平滑肌松弛。 一种新的方法将 用于研究气道存在时SNO向NO的转化 细胞 使用该系统的初步数据表明， 催化GSNO分解的上皮细胞蛋白。 这些蛋白质 将在尺寸、顺序、反应物和 产物化学计量和动力学。 此外，白细胞介素 4、血管活性肠肽、地塞米松、阿西维星、 金硫葡萄糖和血红蛋白对上皮GSNO催化剂的影响， 将研究氮氧化物的运输。 最后，相关性 将在豚鼠的生物测定中研究上皮GSNO分解 气道平滑肌松弛 总之，本项目将测试 总体假设，GSNO介导的气道平滑肌松弛 在气道上皮细胞存在的情况下， 催化GSNO催化剂的蛋白质。 如果这个假设被证实， GSNO催化剂的预防可以定义新的哮喘疗法。

S-Nitrosothiols (SNOs) in general - and S-nitrosoglutathione (GSNO) in particular - are stable, potent bronchodilators which also have immune regulatory functions and are present in the normal human airway. Asthmatic bronchospasm is associated with paradoxically low airway SNO levels - and undetectable GSNO levels - despite relatively high concentrations of nitric oxide ( NO) in expired air and upregulation of inducible-nitric oxide synthase. This paradox may be best explained by considering GSNO to be a reservoir of bioactive nitrogen oxides in the airway - as it is in brain and other tissues - the breakdown of which is accelerated in asthma. In this sense, airway SNO catabolism may contribute both to high expired NO concentrations and to bronchospasm in asthmatic patients. This project will test the hypotheses that 1) airway epithelial cells catabolize SNO; 2) the SNO catabolic activity of airway epithelial cells is altered by stimulants relevant to asthma pathophysiology; and 3) airway epithelial cell-mediated SNO catabolism inhibits airway smooth muscle relaxation. A new methodology will be used to study the conversion of SNO to NO in the presence of airway cells. Preliminary data using this system suggest that there are epithelial cell proteins which catalyze GSNO breakdown. These proteins will be characterized with regard to size, sequence, reactant and product stoichiometry and kinetics. Further, the effects of interleukin 4, vasoactive intestinal peptide, dexamethasone, acivicin, aurothioglucose and hemoglobin on epithelial GSNO catabolism and nitrogen oxide transport will be investigated. Finally, the relevance of epithelial GSNO breakdown will be studied in a bioassay of guinea-pig airway smooth muscle relaxation. In summary, this project will test the overall hypothesis that GSNO-mediated relaxation of airway smooth muscle is inhibited in the presence of airway epithelial cells by a regulated protein which catalyzes GSNO catabolism. If this hypothesis is proven, prevention of GSNO catabolism may define new asthma therapies.