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

• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670618/
• 关键词: nitric oxide (NO); airway responsiveness; airway inflammation; asthma; L-NAME; 気管支喘息; 気道過敏性; NO; i-NANC; 好酸球; ピークフロー; 誘発喀痰; 吸入ステロイド

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，我们测量了在nw -硝基- l -精氨酸甲酯（L-NAME）或神经节阻滞剂六甲铵（据报道可阻断I-NANC）前后向气道输送5 -羟色胺气溶胶所产生的总肺阻力（RL）的变化。之所以选择血清素，是因为它在一定程度上通过神经反射导致支气管收缩。为了进一步阐明其中的机制，我们还测定了吸入辣椒素对阿托品和心得安治疗后5 -羟色胺引起的持续支气管收缩的动物的影响。L-NAME抑制NO合成酶或六甲溴铵阻断I-NANC神经元可显著提高气道反应性。然而，添加L-NAME并没有进一步增加六甲溴铵治疗动物的气道反应性。在阿托品和普萘酚的存在下，吸入辣椒素在血清素诱导的持续支气管收缩期间引起了明显的支气管扩张。六甲溴铵和L-NAME均能显著抑制辣椒素所致的支气管扩张。这些结果表明，I-NANC神经元释放的NO在体内调节猫气道反应性中起重要作用。另一方面，哮喘患者呼出的空气中一氧化氮增加。我们假设内源性NO有助于气道炎症和高反应性，而白细胞介素-8 （IL-8）可能参与了这一机制。在体外转化的人支气管上皮细胞中，NO供体增加IL-8的产生呈剂量依赖性。肿瘤坏死因子-a + IL-1b +干扰素-g可使上皮细胞培养上清中IL-8升高；NO合成酶抑制剂、氨基胍和ng -硝基- l -精氨酸甲酯（L-NAME）联合使用可减弱细胞因子诱导的上皮细胞IL-8的产生。在豚鼠体内，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，这些变化持续至少5小时。预处理NO合成酶抑制剂对臭氧后气道的高反应性和中性粒细胞的积累没有影响，但明显抑制臭氧后5小时的变化。一氧化氮合酶抑制剂还能降低臭氧作用后5 h豚鼠支气管肺泡灌洗液中亚硝酸盐/硝酸盐水平的升高以及上皮细胞和中性粒细胞中IL-8 mRNA的表达。这些结果表明，内源性NO可能在臭氧暴露后持续气道炎症和高反应性中发挥重要作用，可能部分通过上调IL-8。少

项目成果

相沢久道: "NOと気道上皮" アレルギー科. 3. 361-368 (1997)

Hisamichi Aizawa：“NO 和气道上皮细胞”过敏系 3. 361-368 (1997)。

Aizawa H: "L-NAME-sensitive and-insensitive NANC relaxation of cat airway in vivo and intro." European Respiratory Journal. 10(2). 314-321 (1997)

Aizawa H：“猫气道的 L-NAME 敏感和不敏感 NANC 松弛体内和介绍。”

Aizawa H. et. Al.: "Role of nitric oxide in airway inflammation and hyperresponsiveness in bronchial asthma"Allergology International. 48. 25-30 (1999)

相泽 H.等人。

Inoue H.他: "Nitric oxide synthase inhibitors attenuate ozne-induced airway inflammation in guineapigs.possible role of interleukin-8"American Journal of Respiratory and Critical Care Medicine. 161. 249-256 (2000)

Inoue H.等人：“一氧化氮合成酶抑制剂可减轻豚鼠中臭氧引起的气道炎症。白介素-8的可能作用”美国呼吸与重症监护医学杂志 161. 249-256 (2000)。

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Matsumoto K：“肾上腺素能神经系统在香烟烟雾引起的豚鼠支气管收缩中的作用。”