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

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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.