Mechanisms to induce bronchial asthma - an approach by means of molecular biology clarify how airway hyperresponsiveness is expressed with air pollutants in mice

为了阐明诱发支气管哮喘的机制，我们一直专注于气道高反应性的表达作为哮喘的特征之一，并一直在研究小鼠模型，我们可以评估气道对乙酰胆碱（Ach）的反应性。本研究于1994年至1995年进行了2年的研究，试图阐明空气污染物，一组重要的生理刺激，如何在我们的小鼠模型中诱导气道高反应性，特别是集中在细胞和细胞因子。结果表明：（1）将空气污染物如二氧化氮的液态转化产物硝酸和柴油机尾气颗粒物（DEP）注入气道，可诱导先天性高反应性（A/J）和低反应性（Balb/c和C57 Bl/6）小鼠的气道高反应性。2)在肥大细胞缺陷株W/W^V中，空气污染物（硝酸和DEP）对气道反应的增强作用部分受到抑制，表明肥大细胞发挥了一些作用，但不是主要作用。3)抗GM-CSF中和抗体可完全抑制A/J小鼠气道对Ach的反应性，提示GM-CSF在气道高反应性的发病机制中起关键作用。此外，GM-CSF的mRNA表达被发现在暴露于空气污染物的肺中上调。4)当我们将GM-CSSF施用到小鼠气道中时，气道反应性显著增加，证实了GM-CSF的功能参与。5）用针对IL-6或IL-8的中和抗体进行的研究没有显示对空气污染物的气道高反应性的显著抑制作用，表明这些因素在诱导气道高反应性中不起中心作用。结论：GM-CSF在支气管哮喘的发病中起重要作用。

In order to clarify the mechanisms for inducing bronchial asthma, we have focused on the expression of airway hyperresponsiveness as one of the characteristic features of asthma, and have been studying a murine model in which we can evaluate airway responsiveness to asetylcholine (Ach). In the present investigation performed for 2 years between 1994 and 1995, we tried to clarify how air pollutants, a group of important physiological stimuli, can induce airway hyperresponsiveness in our murine model especially by concentrating on cells and cytokines. Our results were as follows : 1) Administration into the airway with air pollutants such as nitric acid, a liquid transformation product of nitrogen dioxide, and diesel exhaust particulates (DEP) induced airway hyperresponsiveness in mice of both congenitally hyperresponsive (A/J) and hyporesponsive stains (Balb/c and C57Bl/6). 2) In a mast cell deficient strain, W/W^V, the augmentation of airway response with the air pollutants (nitric acid and DEP) was partially suppressed, suggesting that mast cells play some role but not a major one. 3) Neutralizing antibody to GM-CSF completely inhibited the augmentation of airway responsiveness to Ach with the airpollutants in A/J mice, suggesting a pivotal role of GM-CSF in the pathogenesis of airway hyperresponsiveness. Moreover, the expression of mRNA for GM-CSF was found to be upregulated in the lungs exposed to the airpollutants. 4) When we administered GM-CSSF into the airway in mice, airway responsiveness increased significantly, confirming the functional involvement of GM-CSF.5) Studies with neutralizing antibody to either IL-6 or IL-8 did not show significant inhibitory effects on airway hyperresponsiveness with air pollutants, suggesting that these factors do not play a central role in inducing airway hyperresponsiveness. We conclude that GM-CSF may play an important role in the pathogenesis of bronchial asthma.