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

Abstract

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...

Sensitization by Pulmonary Reactive Oxygen Species of Rat Vagal Lung C-Fibers: The Roles of the TRPV1, TRPA1, and P2X Receptors

“…In these studies [14]–[16], these exaggerated responses could be prevented by pretreatment with antioxidants, indicating that there seemed to be an involvement of ROS in the sensitization of airway C-fibers and the development of airway hypersensitivity. However, questions remained as to whether the suppressive effects of the antioxidants in these studies resulted from a prevention of sensitization of the afferent fibers by the increased ROS or occurred because there was a removal of the basal function of ROS, which led to diminished afferent fiber sensitivity to these airway insults.…”

“…It has been previously shown that acute intermittent hypoxia [14] and laryngeal insult with acid and pepsin [15], [16] are able to potentiate the afferent and/or reflex responses of the airway C-fibers to stimulants in rats; the potentiating effect of the former and latter insults were found to be mediated through the TRPA1 and P2X receptors, respectively. In these studies [14]–[16], these exaggerated responses could be prevented by pretreatment with antioxidants, indicating that there seemed to be an involvement of ROS in the sensitization of airway C-fibers and the development of airway hypersensitivity.…”

“…To this end, three previous studies have provided indirect evidence indicating that there is a cause-effect relationship between ROS and the airway hypersensitivity. Shen et al [14] reported that acute intermittent hypoxia augmented the afferent and reflex responses to stimulants of VLCFs in rats. Tsai et al [15], [16] demonstrated that laryngeal acid-pepsin insult augmented the reflex responses to stimulants of the superior laryngeal C-fibers in rats.…”

“…Additionally, studies investigating the responses of VLCFs to oxidants have suggested that ROS derived from the oxidants may activate these three types of receptors [18], [24]–[27]. Importantly, it has been proposed that these three types of pharmacological receptors have roles in the development of the airway hypersensitivity that is mediated by airway C-fibers [1], [2], [14], [15], [28], [29]. Taken together, these lines of evidence lend support to the possibility that the TRPV1, TRPA1, and P2X receptors are likely to play contributory roles in ROS-induced VLCF-mediated airway hypersensitivity.…”

Human TRPM8 and TRPA1 pain channels, including a gene variant with increased sensitivity to agonists (TRPA1 R797T), exhibit differential regulation by SRC-tyrosine kinase inhibitor

“…For example, TRPM8 (transient receptor potential M8) and TRPA1 (transient receptor potential A1) affect human physiology by initiating responses to volatile chemical agents or cold air via Ca 2+ -mediated activation of the peripheral nervous system, epithelia and underlying tissues [6–8]. They are modulated by specific biochemical species [9,10] or cell stress [11,12] and both TRP channels may be involved in pathological conditions such as asthma, chronic obstructive pulmonary disease and chronic cough [13–16]. Hence they are emerging targets for pharmacological intervention [17].…”