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中气道反应性调节中的作用。为了评估气道响应能力，我们测量了通过在NW-硝基-L-精氨酸甲酯（L-N-NAME）或神经节封闭剂，六甲基甲基甲基甲基甲基酯（L-N-NAME）之前和之后，通过将血清素气溶胶传递到气道产生的总肺电阻（RL）的变化，据报道被封锁了I-Nanc。之所以选择5-羟色胺，是因为它部分由神经反射引起支气管收缩。为了进一步阐明所涉及的机制，我们还确定了遗传性辣椒素在用芳香胺和普萘洛尔治疗后通过血清素诱导的持续支气管收缩的动物的作用。通过L-NAME或通过Hexamethonium抑制I-Nanc神经元的NO合酶的抑制作用可显着提高气道响应能力。但是，添加L名称并没有进一步增加用六甲基治疗的动物中的气道反应能力。在存在阿托品和普罗醇的情况下，更多的OL遗传性辣椒素在血清素引起的持续支气管收缩期间引起了明显的支气管扩张。六面甲基或L-NAME显着抑制了由辣椒素诱导的支气管扩张。这些结果表明，I-NANC神经元释放的NO对于调节体内猫的气道反应性很重要。另一方面，在哮喘患者耗尽的空气中，NO增加了。我们假设内源性没有促进气道感染和反应性高反应性，而白介素-8（IL-8）可能参与了这种机制。在人体转化的支气管上皮细胞体外，没有供体依赖于IL-8产生剂量。此外，肿瘤坏死因子-A加IL-1B加干扰素-G增加了上皮细胞培养上清液中的IL-8。无合酶抑制剂，氨基瓜氨酸加Ng-硝基-L-弧菌甲酯（L-NAME）的组合减弱了细胞因子诱导的上皮细胞中的IL-8产生。在体内豚鼠中，臭氧暴露诱导了气道对乙酰胆碱的高反应性，并在支气管肺泡灌洗液中增加了中性粒细胞，并且这些变化持续至少5小时。没有合成酶抑制剂的预处理对臭氧后立即对气道高反应性或中性粒细胞积累没有影响，但在臭氧后5小时显着抑制了这些变化。没有合成酶抑制剂还会减弱支气管肺泡灌洗液中亚硝酸盐/硝酸盐水平的增加，以及臭氧后5小时的上皮细胞和豚鼠中嗜中性粒细胞中的IL-8 mRNA表达。这些结果表明，内源性NO可能在臭氧暴露后的持续气道注入和反应性过高中起重要作用，大概部分通过IL-8的上调。较少的