Activations of TRPA1 and P2X receptors are important in ROS-mediated stimulation of capsaicin-sensitive lung vagal afferents by cigarette smoke in rats

Lin, Yun‐Sheng; Hsu, Chun‐Chun; Bien, Mauo Ying; Hsu, Hui‐Chun; Weng, Hsu Ting; Kou, Yu Ru

doi:10.1152/japplphysiol.01048.2009

Cited by 45 publications

(53 citation statements)

References 48 publications

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“…Subsequently, the experiments were repeated 15 min after pretreatment with HC-030031 (an antagonist of TRPA1 receptors; 8 mg/kg iv) (groups 8 and 9) or its vehicle (groups 10 and 11). The dose of HC-030031 was shown to exert a complete blocking effect on the stimulation of the CSLV fibers elicited by the TRPA1 receptor agonist in our previous study (25). The purpose of series 6 was to verify the effectiveness and specificity of the antagonizing effect of HC-030031 on the TRPA1 receptors under the present experimental conditions.…”

Section: In Vivo Studymentioning

confidence: 80%

“…Fiber activity arising from CSLV afferents was recorded in the anesthetized, artificially ventilated rats by using the techniques described in our previous studies (14,(25)(26)(27). In brief, the trachea was cannulated and tracheal pressure was measured via a sideport of the cannula.…”

Section: In Vivo Studymentioning

confidence: 99%

“…lung; lung vagal C fibers; afferent sensitization; H2S; TRPA1 receptors CAPSAICIN-SENSITIVE LUNG VAGAL (CSLV) afferents are nociceptive-like free nerve endings innervating all levels of the respiratory tract. CSLV afferents can detect several inhaled irritants (22, 25) and inflammatory mediators (16,25,26,39) that might in turn trigger various respiratory reflexes such as cough, mucus secretion, and bronchoconstriction (7,22). The afferents are sensitized by several mediators released because of lung inflammation (2,7,15,27), which might then exaggerate these respiratory reflexes.…”

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confidence: 99%

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Hydrogen sulfide induces hypersensitivity of rat capsaicin-sensitive lung vagal neurons: role of TRPA1 receptors

Hsu

Lin

Lee

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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-The sensitization of capsaicin-sensitive lung vagal (CSLV) afferents by inflammatory mediators is important in the development of airway hypersensitivity. Hydrogen sulfide (H 2 S) is an endogenous mediator inducing hyperalgesia through transient receptor potential ankyrin 1 (TRPA1) receptors located on nociceptors. We conducted this study to determine whether H 2S elevates the sensitivity of rat CSLV afferents. In anesthetized, artificially ventilated rats, the inhalation of aerosolized sodium hydrosulfide (NaHS, a H2S donor) caused no significant changes in the baseline activity of CSLV afferents. However, the afferent responses to right atrial injection of capsaicin or phenylbiguanide and to lung inflation were all markedly potentiated after NaHS inhalation. By contrast, the inhalation of its vehicle or NaOH (with a similar pH to NaHS) failed to enhance the afferent responses. Additionally, the potentiating effect on the afferent responses was found in rats inhaling L-cysteine (a substrate of H2S synthase) that slowly releases H2S. The potentiating effect of NaHS on the sensitivity of CSLV afferents was completely blocked by pretreatment of HC-030031 (a TRPA1 receptor antagonist) but was unaffected by its vehicle. In isolated rat CSLV neurons, the perfusion of NaHS alone did not influence the intracellular Ca 2ϩ concentration but markedly potentiated the Ca 2ϩ transients evoked by capsaicin. The NaHScaused effect was totally abolished by HC-030031 pretreatment. These results suggest that H2S induces a nonspecific sensitizing effect on CSLV fibers to both chemical and mechanical stimulation in rat lungs, which appears mediated through an action on the TRPA1 receptors expressed on the nerve endings of CSLV afferents. lung; lung vagal C fibers; afferent sensitization; H2S; TRPA1 receptors CAPSAICIN-SENSITIVE LUNG VAGAL (CSLV) afferents are nociceptive-like free nerve endings innervating all levels of the respiratory tract. CSLV afferents can detect several inhaled irritants (22, 25) and inflammatory mediators (16,25,26,39) that might in turn trigger various respiratory reflexes such as cough, mucus secretion, and bronchoconstriction (7,22). The afferents are sensitized by several mediators released because of lung inflammation (2,7,15,27), which might then exaggerate these respiratory reflexes. Therefore, the sensitization of CSLV afferents is probably involved in the pathogenesis of airway hypersensitivity in diseases such as chronic cough and asthma (7, 26, 47).Hydrogen sulfide (H 2 S), an irritant gas with the smell of rotten eggs, is emitted principally from volcanoes, hot springs, and numerous industrial sites. Lung exposure to H 2 S might lead to adverse respiratory effects, such as cough, airway irritation, airway hypersensitivity, and lung inflammation (16, 37, 41). Therefore, for the past decades, H 2 S was generally considered only an exogenous irritant. However, beginning with a report in 1996, H 2 S was suggested to act as an endogenous neuromodulator facilitating the hippocampal long-term potentiati...

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Section: In Vivo Studymentioning

confidence: 80%

Section: In Vivo Studymentioning

confidence: 99%

mentioning

confidence: 99%

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Hydrogen sulfide induces hypersensitivity of rat capsaicin-sensitive lung vagal neurons: role of TRPA1 receptors

Hsu

Lin

Lee

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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“…TRPA1 can be activated by various chemical stimulants, including ROS (5,48). However, production of some arachidonic acid metabolites under oxidative stress may also activate TRPA1 receptors and then cause stimulation of LVCFs (33). Our results obtained from measurements of reflex apneic response and single-unit LVCF recording have demonstrated that administration of TRPA1 antagonists (HC-030031 or AP18) prevented the AIH-enhanced reflex apnea and LVCF sensitivity to capsaicin and ␣,␤-methylene-ATP.…”

Section: Discussionmentioning

confidence: 63%

“…Pretreatments with dimethylthiourea, Nacetyl-L-cysteine, vehicle of antioxidants, HC-030031, AP18, and vehicle of TRPA1 antagonists were made 15, 15, 15, 5, 5, and 5 min, respectively, before AIH exposure. The doses and treatment times with effectiveness for these drugs were adopted from previous studies (28,33).…”

Section: Methodsmentioning

confidence: 99%

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

Shen

Luo

Yang

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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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...

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Sensory Nerves in Lung and Airways

Lee

2014

Comprehensive Physiology

113

157

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Sensory nerves innervating the lung and airways play an important role in regulating various cardiopulmonary functions and maintaining homeostasis under both healthy and disease conditions. Their activities conducted by both vagal and sympathetic afferents are also responsible for eliciting important defense reflexes that protect the lung and body from potential health-hazardous effects of airborne particulates and chemical irritants. This article reviews the morphology, transduction properties, reflex functions, and respiratory sensations of these receptors, focusing primarily on recent findings derived from using new technologies such as neural immunochemistry, isolated airway-nerve preparation, cultured airway neurons, patch-clamp electrophysiology, transgenic mice, and other cellular and molecular approaches. Studies of the signal transduction of mechanosensitive afferents have revealed a new concept of sensory unit and cellular mechanism of activation, and identified additional types of sensory receptors in the lung. Chemosensitive properties of these lung afferents are further characterized by the expression of specific ligand-gated ion channels on nerve terminals, ganglion origin, and responses to the action of various inflammatory cells, mediators, and cytokines during acute and chronic airway inflammation and injuries. Increasing interest and extensive investigations have been focused on uncovering the mechanisms underlying hypersensitivity of these airway afferents, and their role in the manifestation of various symptoms under pathophysiological conditions. Several important and challenging questions regarding these sensory nerves are discussed. Searching for these answers will be a critical step in developing the translational research and effective treatments of airway diseases.

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Activations of TRPA1 and P2X receptors are important in ROS-mediated stimulation of capsaicin-sensitive lung vagal afferents by cigarette smoke in rats

Cited by 45 publications

References 48 publications

Hydrogen sulfide induces hypersensitivity of rat capsaicin-sensitive lung vagal neurons: role of TRPA1 receptors

Hydrogen sulfide induces hypersensitivity of rat capsaicin-sensitive lung vagal neurons: role of TRPA1 receptors

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

Sensory Nerves in Lung and Airways

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