Chlorpyrifos-Induced Airway Hyperreactivity in Rats Is Dependent on NK1 Receptor Signaling

Abstract

Occupational and environmental exposures to organophosphorus pesticides (OP) are associated with increased asthma incidence. While the canonical mechanism of OP neurotoxicity is acetylcholinesterase (AChE) inhibition, we previously demonstrated that the OP chlorpyrifos (CPF) causes airway hyperreactivity (AHR) in adult rats 24 h after exposure at levels that do not significantly inhibit AChE. Here we further investigated the persistence of CPF-induced AHR at 7 days post-exposure and tested the hypothesis that neurogenic inflammation contributes to CPF-induced AHR. Eight-week-old male Sprague Dawley rats were administered 30 mg/kg CPF subcutaneously, and AHR was assessed at 24 h or 7 days post-exposure using a Flexivent mechanical ventilator during electrical stimulation of the vagus nerves. CPF significantly increased airway resistance and elastance at 24 h and 7 days post-exposure. The NK1 antagonist SR140333 was used to evaluate the involvement of substance P and its receptor NK1 in CPF-induced AHR. SR140333 was injected into rats 1 h before mechanical ventilation and vagal stimulation. NK1 receptor inhibition decreased vagally stimulated bronchoconstriction in CPF-exposed male animals to that observed in vehicle controls, at 24 h and 7 days post-CPF exposure. These data suggest that substance P signaling contributes to both acute and persistent CPF-induced AHR. These findings have significant implications for assessing the risk to human health and safety of CPF, and potentially other OPs, and indicate a potential new therapy for mitigating AHR in intoxicated individuals. This work was supported by the NIH (grants R01 ES017592 and T32 HL07013). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.