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

Abstract

-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...

Role of Dysregulated Ion Channels in Sensory Neurons in Chronic Kidney Disease-Associated Pruritus

“…Wilson et al showed that TRPA1 is the downstream target of both mas-related GPCR (Mrgpr) A3 and Mrgprc11, which act as receptors for the pruritogens chloroquine and BAM8-22, respectively [29]. However, no TRPA1 expression was observed regardless of CKD-aP, suggesting that TRPA1 may be down-regulated by intracellular signals of itch such as H 2 S [30]. Uremic toxins stimulate the production of ROS, such as H 2 O 2 , in mitochondria [4,5].…”

Chronic Kidney Disease–Associated Pruritus is Caused by Dysregulated Ion Channels in Sensory Neurons

“…Wilson et al showed that TRPA1 is the downstream target of both masrelated GPCR (Mrgpr) A3 and Mrgprc11, which act as receptors for the pruritogens chloroquine and BAM8-22, respectively [25]. But no TRPA1 expression was observed regardless of CKD-aP, suggesting that TRPA1 may be downregulated by intracellular signals of itch such as H2S [26]. Uremic toxins stimulate the production of ROS, such as H2O2, in mitochondria [27,28].…”

Effects of sulfide and polysulfides transmitted by direct or signal transduction‐mediated activation of TRPA1 channels

“…No individual excitatory action but potentiation of the capsaicin‐induced response by NaHS was reported in isolated vagal neurons from rat lungs . Even in this model, respiratory effects of sulfide could be abolished by HC030031 (Hsu et al ., ). CGRP release from peptidergic nerves of rat tracheae was reported in response to stimulation with NaHS.…”