Sensitization by pulmonary reactive oxygen species of rat vagal lung C-fibers: the roles of the TRPV1, TRPA1, and P2X receptors.
Sensitization of vagal lung C-fibers (VLCFs) induced by mediators contributes to the pathogenesis of airway hypersensitivity, which is characterized by exaggerated sensory and reflex responses to stimulants. Reactive oxygen species (ROS) are mediators produced during airway inflammation. However, the role of ROS in VLCF-mediated airway hypersensitivity has remained elusive. Here, we report that inhalation of aerosolized 0.05% H2O2 for 90 s potentiated apneic responses to intravenous capsaicin (a TRPV1 receptor agonist), α,β-methylene-ATP (a P2X receptor agonist), and phenylbiguanide (a 5-HT3 receptor agonist) in anesthetized rats. The apneic responses to these three stimulants were abolished by vagatomy or by perivagal capsaicin treatment, a procedure that blocks the neural conduction of VLCFs. The potentiating effect of H2O2 on the apneic responses to these VLCF stimulants was prevented by catalase (an enzyme that degrades H2O2) and by dimethylthiourea (a hydroxyl radical scavenger). The potentiating effect of H2O2 on the apneic responses to capsaicin was attenuated by HC-030031 (a TRPA1 receptor antagonist) and by iso-pyridoxalphosphate-6-azophenyl-2',5'-disulphonate (a P2X receptor antagonist). The potentiating effect of H2O2 on the apneic responses to α,β-methylene-ATP was reduced by capsazepine (a TRPV1 receptor antagonist), and by HC-030031. The potentiating effect of H2O2 on the apneic responses to phenylbiguanide was totally abolished when all three antagonists were combined. Consistently, our electrophysiological studies revealed that airway delivery of aerosolized 0.05% H2O2 for 90 s potentiated the VLCF responses to intravenous capsaicin, α,β-methylene-ATP, and phenylbiguanide. The potentiating effect of H2O2 on the VLCF responses to phenylbiguanide was totally prevented when all antagonists were combined. Inhalation of 0.05% H2O2 indeed increased the level of ROS in the lungs. These results suggest that 1) increased lung ROS sensitizes VLCFs, which leads to exaggerated reflex responses in rats and 2) the TRPV1, TRPA1, and P2X receptors are all involved in the development of this airway hypersensitivity.
School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; Department of Physiology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Ting
T
Ruan
Department of Physiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Yu-Jung
YJ
Lin
Department of Veterinary Medicine, National Chung-Hsing University, Taichung, Taiwan.
Tien-Huan
TH
Hsu
Department of Urology, Taipei City Hospital, Zhong-Xiao Branch, Taipei, Taiwan.
Shing-Hwa
SH
Lu
School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan.
Guey-Mei
GM
Jow
Department of Physiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Yu Ru
YR
Kou
D000818:Animals; D001049:Apnea / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid; D004594:Electrophysiology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008168:Lung / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008297:Male; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D012123:Pulmonary Ventilation / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D058469:Receptors, Purinergic P2X / Q000378:metabolism*; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism*; D014630:Vagus Nerve / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism
D016877:Oxidants; D017382:Reactive Oxygen Species; D058469:Receptors, Purinergic P2X; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D050916:TRPV Cation Channels; C480976:Trpa1 protein, rat; C493922:Trpv1 protein, rat; D006861:Hydrogen Peroxide