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

诱发支气管哮喘的机制——一种分子生物学方法阐明小鼠空气污染物如何表达气道高反应性

基本信息

批准号：
06670631
负责人：
OHTA Ken
金额：
$ 1.34万
依托单位：
Teikyo University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

项目摘要

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.

为了明确支气管哮喘的诱导机制，我们将气道高反应性作为哮喘的特征之一，并研究了一种小鼠模型，我们可以评估气道对乙酰胆碱（Ach）的反应性。在1994年至1995年间进行的为期2年的研究中，我们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，特别是通过集中于细胞和细胞因子。我们的研究结果如下：1)将空气污染物如硝酸（二氧化氮的液体转化产物）和柴油废气颗粒（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C57Bl/6）小鼠气道高反应性。2)在肥大细胞缺陷菌株W/W^V中，空气污染物（硝酸和DEP）对气道反应的增强被部分抑制，表明肥大细胞在其中起一定作用，但不是主要作用。3) GM-CSF中和抗体完全抑制A/J小鼠气道对空气污染物乙酰胆碱的反应性增强，提示GM-CSF在气道高反应性发病机制中起关键作用。此外，GM-CSF mRNA的表达在暴露于空气污染物的肺中被发现上调。4)将GM-CSSF注入小鼠气道后，气道反应性明显增强，证实GM-CSF的功能参与。5) IL-6或IL-8中和抗体对气道对空气污染物的高反应性均无明显抑制作用，提示这些因素在诱导气道高反应性中并非起核心作用。我们认为GM-CSF可能在支气管哮喘的发病机制中起重要作用。