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.

The Influence of Sensitization on Mechanisms of Organophosphorus Pesticide–Induced Airway Hyperreactivity

“…A single subcutaneous injection of the OPs, parathion, diazinon, or chlorpyrifos, causes airway hyperreactivity in guinea pigs 24 hours later by inhibiting M2 receptor function on parasympathetic nerves, independent of AChE inhibition (14)(15)(16). These receptors normally inhibit ACh release; thus, M2 loss increases ACh release, resulting in increased vagally induced bronchoconstriction.…”

“…Although agricultural workers are more often nonatopic than individuals working in other sectors or living in urban areas (22), occupational exposure to OPs is associated with increased allergic asthma in agricultural workers (23,24). In nonsensitized guinea pigs, parathioninduced airway hyperreactivity and M2 muscarinic receptor dysfunction is not mediated by eosinophils (14), but instead by TNF-a (15). In guinea pigs sensitized to ovalbumin, a model of atopy, the mechanism of parathion-induced airway hyperreactivity, is changed to be mediated by IL-5 (14).…”

The Pesticide Metabolites Paraoxon and Malaoxon Induce Cellular Death by Different Mechanisms in Cultured Human Pulmonary Cells

“…These changes include, but are not limited to, pulmonary endothelial permeability resulting in pulmonary edema 4 and induction of alveolar macrophage expression of tumor necrosis factor a (TNF-a), causing bronchoconstriction with consequent increases in airway resistance. 26 Clinical autopsy findings associated with acute parathion toxicity include acute emphysema with alveolar endothelial cell morphological changes and significant alveolar endothelial cell death. 27 Histopathological evaluation of these tissues has shown similar morphology to progressive idiopathic pulmonary fibrosis (PIPF) observed with chronic parathion toxicity.…”

Monocrotophos in Gandaman village: India school lunch deaths and need for improved toxicity testing

“…For instance, only a subgroup affects neuropathy target esterase and causes delayed neuropathy (Emerick et al 2012;Ehrich et al 1997). Some organophosphates may be involved in inflammation or inflammatory diseases such as asthma (Proskocil et al 2013;Banks and Lein 2012). Neurodegeneration and spermatotoxicity may be additional side effects Chen et al 2012).…”