MECHANISMS OF HYPERREACTIVITY IN ATOPIC HOSTS

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Under normal circumstances, the release of acetylcholine from airway parasympathetic nerves is limited by inhibitory M2 muscarinic receptors. The negative feedback normally provided by these receptors is decreased or lost in some humans with asthma and in animal models of asthma, leading to hyper-responsiveness. In antigen challenged guinea pigs, we have demonstrated that eosinophils causes M2 receptor dysfunction by releasing major basic protein, which is an allosteric antagonist at the M2 receptor. Hyper-responsiveness can be blocked by an antibody to major basic protein, and can be acutely characterized by airway eosinophilia. Hyper-responsiveness 2 and 3 days after ozone exposure is not blocked by eosinophil depletion, or reversed by heparin, unless the animals are previously sensitized to an antigen. It has recently been demonstrated that the inflammatory response of the lungs may vary depending on the atopic status of the host. It is our hypothesis that the inflammatory response of the lungs to injury, and the mechanisms by which the inflammation causes airway hyper-responsiveness and dysfunction of inhibitory M2 muscarinic receptors, depends upon whether the host is atopic. We postulate that in an animal model of atopy (sensitization to ovalbumin by intraperitoneal injection without inhalational challenge), subsequent ozone exposure will cause an influx of eosinophils. This will be accompanied by M2 receptor dysfunction and by hyper- responsiveness lasting a minimum of 3 days with characteristics more similar to those seen after antigen challenge (i.e., will be blocked by depletion of eosinophils, and will be reversed by heparin). In this grant we will also examine whether development of hyperresponsiveness to ozone in humans is dependent upon atopic status. These data will identify the mechanism behind the different responses of humans to ozone and possibly other air pollutants, thus allowing for better prediction of which individuals are at risk and the development of interventions.