Studies fro the role of nitric oxide in bronchial asthma

一氧化氮在支气管哮喘中作用的研究

基本信息

批准号：
09670618
负责人：
AIZAWA Hisamichi
金额：
$ 1.79万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

项目摘要

We studied the role of nitric oxide (NO) in the regulation of airway responsiveness in anesthetized and mechanically ventilated cats. To assess airway responsiveness, we measured the changes in total pulmonary resistance (RL) produced by delivering serotonin aerosol to the airways before and after Nw-nitro-L-arginine methyl ester (L-NAME), or ganglionic blocker, hexamethonium which was reported to block I-NANC. Serotonin was chosen because it causes bronchoconstriction in part by neural reflex. To further clarify the mechanism (s) involved, we also determined the effect of inhaled capsaicn in the animals with sustained bronchoconstriction induced by serotonin after treatment with atropine and propranolol. Inhibition of NO synthase by L-NAME or blockade of I-NANC neurons by hexamethonium significantly increased airway responsiveness. However, addition of L-NAME did not further increase airway responsiveness in animals treated with hexamethonium. In the presence of atropine and propranol … More ol, inhaled capsaicin caused a marked bronchodilation during serotonin-induced sustained bronchoconstriction. The bronchodilation induced by capsaicin was significantly suppressed by hexamethonium or by L-NAME. These results suggest that the NO released from I-NANC neurons is important in modulating the airway responsiveness of cats in vivo.On the other hand, NO is increased in exhaled air of asthmatics. We hypothesized that endogenous NO contributes to airway inflammation and hyperresponsiveness, and that interleukin-8 (IL-8) might be involved in this mechanism. In human transformed bronchial epithelial cells in vitro, NO donors increased IL-8 production dose-dependently. In addition, tumor necrosis factor-a plus IL-1b plus interferon-g increased IL-8 in culture supernatant of epithelial cells ; the combination of NO synthase inhibitors, aminoguanidine plus NG-nitro-L-argiine methyl ester (L-NAME), attenuated the cytokines-induced IL-8 production in epithelial cells. In guinea pigs in vivo, ozone exposure induced airway hyperresponsiveness to acetylcholine and increased neutrophils in bronchoalveolar lavage fluid, and these changes were persisted for at least 5 h. Pretreatment with NO synthase inhibitors had no effect on airway hyperresponsiveness or neutrophil accumulation immediately after ozone, but significantly inhibited the changes 5 h after ozone. NO synthase inhibitors also attenuated the increases of nitrite/nitrate levels in bronchoalveolar lavage fluid and the IL-8 mRNA expression in epithelial cells and in neutrophils in guinea pig airways 5 h after ozone. These results suggest that endogenous NO may play an important role in the persistent airway inflammation and hyperresponsiveness after ozone exposure, presumably partly through the upregulation of IL-8. Less

我们研究了一氧化氮 (NO) 在麻醉和机械通气猫气道反应性调节中的作用。为了评估气道反应性，我们测量了向气道输送血清素气雾剂前后产生的总肺阻力 (RL) 的变化。 Nw-硝基-L-精氨酸甲酯 (L-NAME) 或神经节阻断剂六甲铵，据报道可阻断 I-NANC。选择血清素是因为它部分地通过神经反射引起支气管收缩。为了进一步阐明所涉及的机制，我们还确定了吸入辣椒素对经阿托品和普萘洛尔抑制后由血清素诱导的持续支气管收缩的动物的影响。 L-NAME 合成酶或六甲铵阻断 I-NANC 神经元显着增加气道反应性，但添加 L-NAME 并没有增加气道反应性。进一步增加用六甲铵治疗的动物的气道反应性，在血清素诱导的持续支气管收缩期间，吸入辣椒素引起显着的支气管扩张。六甲铵或 L-NAME 显着抑制辣椒素引起的支气管扩张。这些结果表明，I-NANC 神经元释放的 NO 对于调节猫的气道反应性非常重要。另一方面，哮喘患者呼出的空气中 NO 增加，我们发现内源性 NO 会导致气道炎症和高反应性，而人转化的支气管上皮细胞中的白介素 8 (IL-8) 可能参与其中。在体外细胞中，NO 供体增加了 IL-8 的产生，剂量依赖性此外，肿瘤坏死因子-a 加 IL-1b 加干扰素-g 增加了培养物上清液中的 IL-8。上皮细胞的NO合酶抑制剂、氨基胍加NG-硝基-L-精氨酸甲酯(L-NAME)的组合，减弱了豚鼠体内上皮细胞中细胞因子诱导的IL-8的产生，臭氧暴露诱导。气道对乙酰胆碱的高反应性和支气管肺泡灌洗液中中性粒细胞的增加，并且这些变化持续存在NO合酶抑制剂预处理对臭氧后气道高反应性或中性粒细胞积聚没有影响，但在臭氧后5小时显着抑制变化，也减弱了支气管肺泡灌洗液中亚硝酸盐/硝酸盐水平的增加。臭氧处理后 5 小时，豚鼠呼吸道上皮细胞和中性粒细胞中 IL-8 mRNA 的表达。表明内源性 NO 可能在臭氧暴露后的持续气道炎症和高反应性中发挥重要作用，部分原因可能是通过 IL-8 的上调。