Ozone-induced hyperresponsiveness and blockade of M2 muscarinic receptors by eosinophil major basic protein

Control of airway smooth muscle is provided by parasympathetic nerves that release acetylcholine onto M-3 muscarinic receptors. Acetylcholine release is limited by inhibitory M-2 muscarinic receptors. In antigen-challenged gu inea pigs, hyperresponsiveness is due to blockade of neuronal M-2 receptors by eosinophil major basic protein (MBP). Because exposure of guinea pigs t o ozone also causes M-2 dysfunction and airway hyperresponsiveness, the rol e of eosinophils in ozone-induced hyperresponsiveness was tested. Animals w ere exposed to filtered air or to 2 parts/million ozone for 4 h. Twenty-fou r hours later, the muscarinic agonist pilocarpine no longer inhibited vagal ly induced bronchoconstriction in ozone-exposed animals, indicating M-2 dys function. M-2 receptor function in ozone-exposed animals was protected by d epletion of eosinophils with antibody to interleukin-5 and by pretreatment with antibody to guinea pig MBP. M-2 function was acutely restored by remov al of MBP with heparin. Ozone-induced hyperreactivity was also prevented by antibody to MBP and was reversed by heparin. These data show that loss of neuronal M-2 receptor function after ozone is due to release of eosinophil MBP.