Abstract
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.
Highlights
Patients with asthma display airway hypersensitivity, which is characterized by exaggerated sensory and reflex responses to inhaled irritants and chemical mediators [1,2,3]
The results of this study demonstrate that inhalation of aerosolized 0.05% H2O2 for 90 s in anesthetized rats potentiated the apneic responses to intravenous injection of three chemical stimulants: capsaicin, a,b-meATP, and phenylbiguanide
The apneic responses to these three stimulants were abolished by vagatomy or perivagal capsaicin treatment, which suggests the responses are reflex consequences mediated through the Vagal lung C-fibers (VLCFs)
Summary
Patients with asthma display airway hypersensitivity, which is characterized by exaggerated sensory and reflex responses to inhaled irritants and chemical mediators [1,2,3]. Asthmatic lungs exhibit increased oxidative stress, which is partly due to excess production of reactive oxygen species (ROS) [4,5]. The majority of the ROS are superoxide anion radicals, hydrogen peroxide (H2O2) and hydroxyl radicals (NOH) [6]. The superoxide anion radical dismutates to form H2O2, which in the presence of iron can further react to form more reactive NOH via the Fenton reaction [6]. The level of H2O2, a relatively stable ROS, in exhaled breath condensate has been shown to be increased in patients with asthma [7,8]. While ROS have been suggested to play a role in the pathogenesis of asthma [4,5], their involvement in the development of the airway hypersensitivity remains elusive
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