title: Macrophage TNF-α mediates parathion-induced airway hyperreactivity in guinea pigs.
abstract: Organophosphorus pesticides (OPs) are implicated in human asthma. We previously demonstrated that, at concentrations that do not inhibit acetylcholinesterase activity, the OP parathion causes airway hyperreactivity in guinea pigs as a result of functional loss of inhibitory M2 muscarinic receptors on parasympathetic nerves. Because macrophages are associated with asthma, we investigated whether macrophages mediate parathion-induced M2 receptor dysfunction and airway hyperreactivity. Airway physiology was measured in guinea pigs 24 h after a subcutaneous injection of parathion. Pretreatment with liposome-encapsulated clodronate induced alveolar macrophage apoptosis and prevented parathion-induced airway hyperreactivity in response to electrical stimulation of the vagus nerves. As determined by qPCR, TNF-α and IL-1β mRNA levels were increased in alveolar macrophages isolated from parathion-treated guinea pigs. Parathion treatment of alveolar macrophages ex vivo did not significantly increase IL-1β and TNF-α mRNA but did significantly increase TNF-α protein release. Consistent with these data, pretreatment with the TNF-α inhibitor etanercept but not the IL-1β receptor inhibitor anakinra prevented parathion-induced airway hyperreactivity and protected M2 receptor function. These data suggest a novel mechanism of OP-induced airway hyperreactivity in which low-level parathion activates macrophages to release TNF-α-causing M2 receptor dysfunction and airway hyperreactivity. These observations have important implications regarding therapeutic approaches for treating respiratory disease associated with OP exposures.
authors: Division of Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, OR 97239, USA. proskoci@ohsu.edu
authors: Becky J
authors: BJ
authors: Proskocil
authors: Donald A
authors: DA
authors: Bruun
authors: David B
authors: DB
authors: Jacoby
authors: Nico
authors: N
authors: van Rooijen
authors: Pamela J
authors: PJ
authors: Lein
authors: Allison D
authors: AD
authors: Fryer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016535:Bronchial Hyperreactivity / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004002:Clodronic Acid / Q000494:pharmacology; D000068800:Etanercept; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007306:Insecticides / Q000633:toxicity; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D010278:Parathion / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043585:Receptor, Muscarinic M2 / Q000819:agonists / Q000037:antagonists & inhibitors; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*
chemical_list: D007074:Immunoglobulin G; D007306:Insecticides; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D012333:RNA, Messenger; D043585:Receptor, Muscarinic M2; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D004002:Clodronic Acid; D010278:Parathion; D000068800:Etanercept
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