Diesel exhaust particulate induces airway hyperresponsiveness in a murine model: Essential role of GM-CSF

Background: Inhaled pollutants were recently shown to be responsible for an increased incidence of airway allergic diseases, including asthma. A commo n feature of all forms of asthma is airway hyperresponsiveness. Objective: Our purpose was to elucidate the effects of diesel exhaust parti culate (DEP), one of the most prevalent inhaled pollutants, on airway respo nsiveness. Methods: A/J and C57Bl/6 mice were used; the former are genetically predisp osed to be hyperresponsive to acetylcholine, whereas the latter are not. DE P was administered intranasally for 2 weeks, after which pulmonary function was analyzed by whole-body plethysmography. Results: Intranasal administration of DEP increased airway responsiveness t o acetylcholine in both A/J and C57Bl/6 mice and induced displacement of ci liated epithelial cells by mucus-secreting Clara cells. The effect was medi ated by M-3 muscarinic receptors. Acetylcholine-evoked bronchial constricti on was reversed by administration of terbutaline, a beta(2)-adrenergic anta gonist, which is also characteristic of human asthma. Intranasal administra tion of antibody raised against GM-CSF abolished DEP-evoked increases in ai rway responsiveness and Clara cell hyperplasia. The antibody raised against IL-4 also inhibited DEP-evoked increases in airway responsiveness. However , it was to a lesser extent compared with antibody against GM-CSF In additi on, DEP stimulated GM-CSF messenger RNA expression in the lung. Conclusion DEP induces airway hyperresponsiveness by stimulating GM-CSF syn thesis.