Mutual Interaction between Airway Inflammation and β-Adrenoceptor Function

气道炎症与 β-肾上腺素受体功能之间的相互作用

• 批准号: 11670581
• 负责人: KOTO Hiroshi
• 金额: $ 2.3万
• 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: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670581/
• 关键词: Bronchial Asthma; Airway Inflammation; β-Adrenoceptor; β受容体; G蛋白; アデニル酸シクラーゼ; オゾン

We first investigated the mechanism by which acute ozone exposure (3 ppm for 2 hours) induces cytokine-induced neutrophil chemoattractant (CINC), a rat homologue of human IL-8. After ozone exposure, CINC concentration in bronchoalveolar lavage fluid (BALF) markedly increased. This induction of CINC protein was significantly attenuated by pretreatment with a tetrapeptide interleukin (IL)-1 beta converting enzyme (ICE) inhibitor, suggesting a pivotal role of endogenous IL-1 beta in this model. (manuscript submitted)We then examined the change in beta-adrenoceptor function after acute ozone exposure. Trachea and lung tissues were excised 24-hour after ozone. Tracheal smooth muscle and lung tissue strips were mounted in organ baths and isometric tension was monitored. Compared with tissues taken from air-exposed animals, ozone exposure caused reduced relaxation response to isoproterenol. The dysfunction of beta-adrenoceptor was significantly blocked by the pretreatment of tissue strips with pertussis toxin, indicating the receptor uncoupling via an induction of inhibitory G protein (Gi). Because tissue response to forskolin was also reduced, airway inflammation induced by ozone appeared to cause change(s) in the downstream of adenylate cyclase. This finding is analogous to our previous data with exogenous IL-1 instillation. We therefore evaluated the effect of ICE inhibitor and confirmed that inhibition of endogenous IL-1 beta production indeed prevents ozone-induced beta-adrenoceptor dysfunction.We now moved to the evaluation of the effect of beta-adrenal stimulation on airway inflammation. Especially, we have concentrated on the effect of intracellular cyclic AMP accumulation on eosinophil apoptosis. We have already confirmed that in vitro incubation with isoproterenol inhibits apoptosis of eosinophils, recovered from mice sensitized and challenged to ovalbumin.

我们首先研究了急性臭氧暴露（3 ppm，2小时）诱导大鼠白细胞介素-8同源物-臭氧暴露后，支气管肺泡灌洗液（BALF）中CINC浓度明显升高。通过用四肽白细胞介素（IL）-1 β转化酶（ICE）抑制剂预处理，CINC蛋白的这种诱导显著减弱，表明内源性IL-1 β在该模型中起关键作用。然后，我们检查了急性臭氧暴露后β-肾上腺素受体功能的变化。臭氧处理后24小时，切除气管和肺组织。将气管平滑肌和肺组织条固定在器官浴中并监测等长张力。与暴露于空气中的动物相比，臭氧暴露导致对异丙肾上腺素的舒张反应降低。用百日咳毒素预处理组织条可显著阻断β-肾上腺素受体的功能障碍，表明通过诱导抑制性G蛋白（Gi）实现受体解偶联。由于组织对毛喉素的反应也降低，臭氧诱导的气道炎症似乎引起腺苷酸环化酶下游的变化。这一发现类似于我们以前的外源性IL-1滴注数据。因此，我们评估了ICE抑制剂的作用，并证实抑制内源性IL-1 β的产生确实可以防止臭氧诱导的β-肾上腺素受体功能障碍。特别是，我们集中在细胞内环AMP积累对嗜酸性粒细胞凋亡的影响。我们已经证实，在体外孵育异丙肾上腺素抑制嗜酸性粒细胞的凋亡，从小鼠致敏和卵白蛋白的挑战。