Mutual Interaction between Airway Inflammation and β-Adrenoceptor Function

我们首先研究了急性臭氧暴露（3ppm持续2小时）诱导细胞因子诱导的中性粒细胞化学引诱物（CINC）的机制，CINC是人类IL-8的大鼠同源物。臭氧暴露后，支气管肺泡灌洗液（BALF）中CINC浓度明显升高。经四肽IL-1 β转换酶（ICE）抑制剂预处理后，这种对CINC蛋白的诱导作用明显减弱，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 -肾上腺素能受体功能的变化。臭氧处理后24小时切除气管和肺组织。气管平滑肌和肺组织条安装在器官浴中，并监测等长张力。与暴露在空气中的动物组织相比，暴露在臭氧中导致对异丙肾上腺素的松弛反应降低。百日咳毒素预处理组织条可显著阻断β -肾上腺素能受体功能障碍，表明受体通过诱导抑制G蛋白（Gi）解偶联。由于组织对福斯克林的反应也降低了，臭氧诱导的气道炎症似乎引起了腺苷酸环化酶下游的变化。这一发现与我们之前外源性IL-1灌注的数据类似。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 -肾上腺素能受体功能障碍。我们现在开始评估肾上腺刺激对气道炎症的影响。特别是，我们集中研究了细胞内环AMP积累对嗜酸性粒细胞凋亡的影响。我们已经证实，异丙肾上腺素体外培养可抑制卵清蛋白致敏小鼠体内嗜酸性粒细胞的凋亡。

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.