Mechanistic Studies Investigating the Role of Organophosphate Insecticide Exposure in the Development and Exacerbation of Asthma

Abstract : This grant proposes to determine whether organophosphate insecticides act upon the cholinergic system in the lungs increasing cholinerqic neurotransmission and causing airway hyperresponsiveness, which is characteristic of asthma. Guinea pigs were either treated acutely with a high dose or chronically (7 days) with a low dose of the organophosphate,chlorpyrifos sc. Electrical stimulation of the vagus nerves caused frequency-dependent bronchoconstriction that was significantly potentiated in animals treated with chlorpyrifos. M2 muscarinic autoreceptors, which normally inhibit release of acetylcholine from cholinergic nerves were dysfunctional in the chlorpyrifos -treated animals. The function of M3 muscarinic receptors on airway smooth muscle was not altered by chlorpyrifos treatment. In addition, the high but not the lower dose of chlorpyrifos significantly inhibited acetylcholinesterase activity, further contributing to airway hyperreactivity. These data demonstrate that organophosphate pesticides are capable of causing airway hyperreactivity by inhibiting neuronal M2 receptor function. A second series of experiments has demonstrated that 2 additional organophoshates, diazinon and paration also inhibit M2 receptor function and cause airway hyperreactivity-, experiments to determine the lowest level of exposure are underway. Thus, we have confirmed that organophosphates cause airway hyperractivity by inhibiting M2 receptor function on the cholinergic nerves and by inhibiting acetylcholinesterase activity.