Division of Pulmonary, Allergy and Critical Care Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Am J Physiol Lung Cell Mol Physiol. 2011 Nov;301(5):L739-44. doi: 10.1152/ajplung.00134.2011. Epub 2011 Jul 22.
S-nitrosoglutathione (GSNO) is an endogenous bronchodilator present in micromolar concentrations in airway lining fluid. Airway GSNO levels decrease in severe respiratory failure and asthma, which is attributable to increased metabolism by GSNO reductase (GSNOR). Indeed, we have found that GSNOR expression and activity correlate inversely with lung S-nitrosothiol (SNO) content and airway hyperresponsiveness (AHR) to methacholine (MCh) challenge in humans with asthmatic phenotypes (Que LG, Yang Z, Stamler JS, Lugogo NL, Kraft M. Am J Respir Crit Care Med 180: 226-231, 2009). Accordingly, we hypothesized that local aerosol delivery of GSNO could ameliorate AHR and inflammation in the ovalbumin-sensitized and -challenged (OVA) mouse model of allergic asthma. Anesthetized, paralyzed, and tracheotomized 6-wk-old male control and OVA C57BL/6 mice were administered a single 15-s treatment of 0-100 mM GSNO. Five minutes later, airway resistance to MCh was measured and SNOs were quantified in bronchoalveolar lavage (BAL). Duration of protection was evaluated following nose-only exposure to 10 mM GSNO for 10 min followed by measurements of airway resistance, inflammatory cells, and cytokines and chemokines at up to 4 h later. Acute delivery of GSNO aerosol protected OVA mice from MCh-induced AHR, with no benefit seen above 20 mM GSNO. The antibronchoconstrictive effects of GSNO aerosol delivered via nose cone were sustained for at least 4 h. However, administration of GSNO did not alter total BAL cell counts or cell differentials and had modest effects on cytokine and chemokine levels. In conclusion, in the OVA mouse model of allergic asthma, aerosolized GSNO has rapid and sustained antibronchoconstrictive effects but does not substantially alter airway inflammation.
S-亚硝基谷胱甘肽（GSNO）是一种内源性的支气管扩张剂，在气道衬液中以微摩尔浓度存在。在严重呼吸衰竭和哮喘中，气道 GSNO 水平下降，这归因于 GSNO 还原酶（GSNOR）的代谢增加。事实上，我们发现 GSNOR 的表达和活性与肺 S-亚硝基硫醇（SNO）含量和对乙酰甲胆碱（MCh）挑战的气道高反应性（AHR）呈负相关，在具有哮喘表型的人群中（Que LG，Yang Z，Stamler JS，Lugogo NL，Kraft M. Am J Respir Crit Care Med 180: 226-231, 2009）。因此，我们假设局部气溶胶输送 GSNO 可以改善卵清蛋白致敏和挑战（OVA）的小鼠模型中的 AHR 和炎症。麻醉、瘫痪和气管切开的 6 周龄雄性对照和 OVA C57BL/6 小鼠接受了 0-100 mM GSNO 的单次 15 秒治疗。5 分钟后，测量 MCh 诱导的气道阻力，并在支气管肺泡灌洗（BAL）中定量 SNO。在鼻暴露于 10 mM GSNO 10 分钟后，评估保护持续时间，然后在多达 4 小时后测量气道阻力、炎症细胞和细胞因子和趋化因子。急性给予 GSNO 气溶胶可防止 OVA 小鼠发生 MCh 诱导的 AHR，在 20 mM GSNO 以上未见获益。GSNO 气溶胶通过鼻锥给药的支气管扩张作用可持续至少 4 小时。然而，GSNO 的给药并未改变总 BAL 细胞计数或细胞差异，并且对细胞因子和趋化因子水平的影响较小。总之，在 OVA 哮喘小鼠模型中，雾化 GSNO 具有快速和持续的支气管扩张作用，但不会显著改变气道炎症。
