Macrophages mediate organophosphorus pesticide‐induced airway hyperreactivity in guinea pigs

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Organophosphorus pesticide (OP) exposure is implicated in human asthma. At doses that do not inhibit acetycholinesterase, OPs such as parathion (Pth) block inhibitory neuronal M2 receptor function, which increases acetylcholine (ACh) release and potentiates vagally‐induced bronchoconstriction in guinea pigs. We tested whether macrophages mediate Pth‐induced airway hyperreactivity. Guinea pig alveolar macrophages were depleted with liposome‐encapsulated dichloromethylene‐diphosphonate (clodronate; prepared by Nico van Rooijen, Amsterdam) given intranasally 1 and 3 days prior to 1.0 mg/kg Pth sc. 24 hrs after Pth administration, animals were anesthetized and ventilated. In non‐Pth treated animals, bronchoconstriction induced by electrical stimulation of both vagus nerves was not affected by clodronate or PBS liposomes. Pth significantly potentiated bronchoconstriction in animals receiving PBS liposomes but did not potentiate bronchoconstriction in those pre‐treated with clodronate. ACh‐induced bronchoconstriction was not affected by any treatment, indicating that smooth muscle responsiveness was not changed. Macrophages mediate Pth‐induced airway hyperreactivity possibly by the release of interferon‐ã which decreases neuronal M2 RNA expression.Funding: NIH ES014521, ES014601, HL55543, HL54659, HL071795