Identification of mechanisms underlying ventilatory dysfunction in organophosphorus chemical warfare agent-exposed mice

Abstract

Chemical warfare nerve agents (CWNA), such as VX, pose significant threats due to their profound impact on vital physiological systems. The primary concern is the risk of respiratory failure resulting from cholinergic dysregulation, a signaling pathway crucial for ventilatory function regulation. This study aims to elucidate the key mechanisms underlying the induction of respiratory failure in mice following sub-lethal VX exposure in order to optimize therapeutic management. We evaluated candidate compounds targeting cholinergic signaling pathways associated with the CWNA poisoning toxidrome or implicated in respiratory disorders with similar symptoms (e.g., asthma or opioid overdose). The efficacy of these compounds in preventing ventilatory abnormalities induced by subcutaneous exposure to 0.9 LD₅₀ of VX was assessed using dual-chamber plethysmography, and survival tests were conducted to confirm their therapeutic effectiveness. Among all the pathways evaluated, only the muscarinic pathway appeared to be involved, with atropine, a standard muscarinic receptor (mAChR) antagonist, which effectively preserved respiratory function by reducing VX-induced bronchoconstriction and preventing respiratory depression. Methylatropine, a peripheral mAChR antagonist that does not cross the blood-brain barrier (BBB), also limited bronchoconstriction but failed to prevent respiratory depression, suggesting that bronchoconstriction is not the primary determinant of this respiratory toxidrome. Surprisingly, tiotropium, a selective M3 mAChR antagonist that also does not cross the BBB, exhibited similar effects to those of atropine. Antagonizing muscarinic pathway overstimulation thus emerges as a key strategy for managing respiratory depression and improving survival outcomes in CWNA-poisoned individuals.