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

Obstructive sleep apnea, manifested by intermittent hypoxia and excess production of reactive oxygen species (ROS) in 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 with acute intermittent hypoxia (AIH), by 10 episodes of exposure to 30 s of hypoxic air (0%, 5%, or 10% O(2)) followed by 30 s of room air in anesthetized, open-chest, and artificially ventilated rats. Reflex apneic response to intravenous capsaicin (an LVCF stimulant), as measured by phrenic nerve activity, was concentration dependently augmented by AIH. Similarly, reflex apneic response to intravenous α,β-methylene-ATP (another LVCF stimulant) was augmented by AIH (0% O(2)). The reflex apnea evoked by these two stimulants was abolished by bilateral vagotomy, which suggests the involvement of lung vagal afferents. The AIH-augmented apneic response to these two stimulants was prevented by pretreatment with dimethylthiourea (a hydroxyl radical scavenger), N-acetyl-l-cysteine (an antioxidant) and HC-030031 [a transient receptor potential ankyrin 1 (TRPA1) receptor antagonist]. Consistently, electrophysiological study revealed the afferent responses of LVCFs to capsaicin or α,β-methylene-ATP were augmented by AIH, and this sensitization of LVCFs was prevented by dimethylthiourea, N-acetyl-l-cysteine, and HC-030031. In contrast, AIH did not alter the afferent response of LVCFs to mechanical stimulation by lung hyperinflation. We concluded that AIH sensitizes LVCFs in rats, thus resulting in exaggerated airway reflexogenic responses to chemical stimulants, possibly by ROS action and activation of TRPA1 receptors.