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Sensitization by pulmonary reactive oxygen species of rat vagal lung C-fibers: the roles of the TRPV1, TRPA1, and P2X receptors.

Ruan T, Lin YJ, Hsu TH, Lu SH, Jow GM, Kou YR - PLoS ONE (2014)

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; Department of Physiology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan.

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.

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Role of vagal lung C-fibers in the sensitizing effect of H2O2 on the apneic responses to intravenous agonists.Data in each panel were obtained from one individual group of rats. Each rat received three consecutive inhalations. Bilateral cervical vagatomy (VG) is a treatment that blocks all vagal afferent pathways. Perivagal capsaicin treatment (PCT; 250 µg/ml) is known to block the neural conduction of vagal lung C-fibers. Perivagal sham treatment (PST) used the vehicle of capsaicin as a substitute for capsaicin. Intravenous agonist injection of capsaicin (A), α,β-meATP (B) or phenylbiguanide (C) was performed at 1 min after inhalation of H2O2 (0.05%) or PBS. Each vagal treatment was made 30 min prior to the second H2O2 sensitization. An elapsed time of 90 min was allowed between any two inhalations. ap<0.05 vs. response before H2O2 sensitization; bp<0.05 vs. response before vagal treatment. Data in each group are the mean ± SE of eight rats. Note that VG or PCT totally abolished the apneic responses to the agonists, while PST had no effect on either the apneic responses to the agonists or the sensitizing effect of H2O2. See legends of figures 1 and 2 for further explanations of H2O2 sensitization, function of agonist, and calculation of the apneic ratio.
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pone-0091763-g003: Role of vagal lung C-fibers in the sensitizing effect of H2O2 on the apneic responses to intravenous agonists.Data in each panel were obtained from one individual group of rats. Each rat received three consecutive inhalations. Bilateral cervical vagatomy (VG) is a treatment that blocks all vagal afferent pathways. Perivagal capsaicin treatment (PCT; 250 µg/ml) is known to block the neural conduction of vagal lung C-fibers. Perivagal sham treatment (PST) used the vehicle of capsaicin as a substitute for capsaicin. Intravenous agonist injection of capsaicin (A), α,β-meATP (B) or phenylbiguanide (C) was performed at 1 min after inhalation of H2O2 (0.05%) or PBS. Each vagal treatment was made 30 min prior to the second H2O2 sensitization. An elapsed time of 90 min was allowed between any two inhalations. ap<0.05 vs. response before H2O2 sensitization; bp<0.05 vs. response before vagal treatment. Data in each group are the mean ± SE of eight rats. Note that VG or PCT totally abolished the apneic responses to the agonists, while PST had no effect on either the apneic responses to the agonists or the sensitizing effect of H2O2. See legends of figures 1 and 2 for further explanations of H2O2 sensitization, function of agonist, and calculation of the apneic ratio.

Mentions: We performed three different vagus nerve treatments to assess the role of VLCFs in airway sensitization by H2O2. As shown in figure 3, the apneic responses to capsaicin (Figure 3A), α,β-meATP (Figure 3B) or phenylbiguanide (Figure 3C) were totally abolished by either bilateral cervical vagatomy (left panels; a treatment that blocks all vagal afferent pathways) or by perivagal capsaicin treatment (middle panels; a treatment that blocks neural conduction of VLCFs) after airway sensitization with 0.05% H2O2. In contrast, the potentiating effect of 0.05% H2O2 on the apneic responses to these three VLCF stimulants was unaffected by perivagal sham treatment (right panels).


Sensitization by pulmonary reactive oxygen species of rat vagal lung C-fibers: the roles of the TRPV1, TRPA1, and P2X receptors.

Ruan T, Lin YJ, Hsu TH, Lu SH, Jow GM, Kou YR - PLoS ONE (2014)

Role of vagal lung C-fibers in the sensitizing effect of H2O2 on the apneic responses to intravenous agonists.Data in each panel were obtained from one individual group of rats. Each rat received three consecutive inhalations. Bilateral cervical vagatomy (VG) is a treatment that blocks all vagal afferent pathways. Perivagal capsaicin treatment (PCT; 250 µg/ml) is known to block the neural conduction of vagal lung C-fibers. Perivagal sham treatment (PST) used the vehicle of capsaicin as a substitute for capsaicin. Intravenous agonist injection of capsaicin (A), α,β-meATP (B) or phenylbiguanide (C) was performed at 1 min after inhalation of H2O2 (0.05%) or PBS. Each vagal treatment was made 30 min prior to the second H2O2 sensitization. An elapsed time of 90 min was allowed between any two inhalations. ap<0.05 vs. response before H2O2 sensitization; bp<0.05 vs. response before vagal treatment. Data in each group are the mean ± SE of eight rats. Note that VG or PCT totally abolished the apneic responses to the agonists, while PST had no effect on either the apneic responses to the agonists or the sensitizing effect of H2O2. See legends of figures 1 and 2 for further explanations of H2O2 sensitization, function of agonist, and calculation of the apneic ratio.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3974698&req=5

pone-0091763-g003: Role of vagal lung C-fibers in the sensitizing effect of H2O2 on the apneic responses to intravenous agonists.Data in each panel were obtained from one individual group of rats. Each rat received three consecutive inhalations. Bilateral cervical vagatomy (VG) is a treatment that blocks all vagal afferent pathways. Perivagal capsaicin treatment (PCT; 250 µg/ml) is known to block the neural conduction of vagal lung C-fibers. Perivagal sham treatment (PST) used the vehicle of capsaicin as a substitute for capsaicin. Intravenous agonist injection of capsaicin (A), α,β-meATP (B) or phenylbiguanide (C) was performed at 1 min after inhalation of H2O2 (0.05%) or PBS. Each vagal treatment was made 30 min prior to the second H2O2 sensitization. An elapsed time of 90 min was allowed between any two inhalations. ap<0.05 vs. response before H2O2 sensitization; bp<0.05 vs. response before vagal treatment. Data in each group are the mean ± SE of eight rats. Note that VG or PCT totally abolished the apneic responses to the agonists, while PST had no effect on either the apneic responses to the agonists or the sensitizing effect of H2O2. See legends of figures 1 and 2 for further explanations of H2O2 sensitization, function of agonist, and calculation of the apneic ratio.
Mentions: We performed three different vagus nerve treatments to assess the role of VLCFs in airway sensitization by H2O2. As shown in figure 3, the apneic responses to capsaicin (Figure 3A), α,β-meATP (Figure 3B) or phenylbiguanide (Figure 3C) were totally abolished by either bilateral cervical vagatomy (left panels; a treatment that blocks all vagal afferent pathways) or by perivagal capsaicin treatment (middle panels; a treatment that blocks neural conduction of VLCFs) after airway sensitization with 0.05% H2O2. In contrast, the potentiating effect of 0.05% H2O2 on the apneic responses to these three VLCF stimulants was unaffected by perivagal sham treatment (right panels).

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; Department of Physiology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan.

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.

Show MeSH
Related in: MedlinePlus