Hypersensitivity of lung vagal C fibers induced by acute intermittent hypoxia in rats: role of reactive oxygen species and TRPA1

Abstract

Obstructive sleep apnea, manifested by intermittent hypoxia and excess production of reactive oxygen species (ROS) in the airways, is associated with hyperreactive airway diseases, but the mechanism remains unclear. Sensitization of lung vagal C fibers (LVCFs) contributes to the airway hypersensitivity. We investigated the mechanisms underlying the sensitization of LVCFs by acute intermittent hypoxia (AIH) for ten episodes of exposure to 30 s of hypoxic air (0, 5 or 10%O2) followed by 30 s of room air in anesthetized, open‐chest, and artificially ventilated rats. Our electrophysiological study revealed that the afferent response of LVCFs to intravenous capsaicin (a LVCF stimulant) was concentration‐dependently augmented by AIH. Similarly, the LVCF responses to α,β‐methylene‐ATP (α,β‐meATP; another LVCF stimulant) was augmented by AIH (0%O2). The AIH‐induced sensitization of LVCFs was prevented by pretreatment with dimethylthiourea (DMTU; a hydroxyl radical scavenger), N‐acetyl‐L‐cysteine (NAC; an antioxidant) or HC‐030031 [a transient receptor potential ankyrin 1 (TRPA1) receptor antagonist]. Contrastingly, AIH failed to alter the afferent response of LVCFs to mechanical stimulation by lung hyperinflation. Our results suggest that AIH sensitizes LVCFs to chemical stimulants in rats possibly via action of ROS and activation of TRPA1 receptors.