of lung vagal C fibers induced by acute intermittent hypoxia in rats: role of reactive oxygen species and TRPA1. Am J Physiol Regul Integr Comp Physiol 303: R1175-R1185, 2012. First published October 17, 2012 doi:10.1152/ajpregu.00227.2012.-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 ␣,␤-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 ␣,␤-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. intermittent hypoxia; lung vagal C fibers; reactive oxygen species; transient receptor potential ankyrin 1 receptors OBSTRUCTIVE SLEEP APNEA (OSA), characterized by intermittent hypoxia during sleep, is associated with several hyperreactive airway diseases, including nocturnal asthma (6, 9), chronic nocturnal cough (10), and bronchial hyperreactivity (32). Patients with OSA generally show airway inflammation (47). Airway hypersensitivity is among the major mechanisms contributing to hyperreactive airways and is manifested by augmented sensory and reflexogenic responses to inhaled irritants or circulating mediators; the hypersensitivity is a prominent pathophysiological feature of airway inflammatory diseases (30, 31). The possible role of sensitization of airway afferents in the OSA-related hyperreactive airway diseases has not been explored.Lung vagal C fibers (LVCFs) are nociceptive-like free nerve endings that are sensitive to various chemicals or inhaled irritants, which leads to activation of various air...

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.