Airway constriction and cough induced by breathing warm humidified air in asthmatics: Role of cholinergic mechanisms

      Transient receptor potential vanilloid type 1 receptor (TRPV1) is a nonselective cation channel and a polymodal transducer, expressed predominantly in non-myelinated sensory nerves. In the respiratory tract, TRPV1 can be activated by a number of inhaled irritants and endogenous chemical mediators. Activation of TRPV1-expressing sensory nerves in the airways is known to elicit cough, cholinergic reflex bronchoconstriction and other pulmonary defense mechanisms. One of the potent physiological stimuli of TRPV1 receptor is high temperature. However, due to the relatively high temperature activation threshold (43 °C) reported in the heterologously expressed TRPV1, its thermal sensitivity in regulating airway function has been largely overlooked. Contrary to this original finding, recent studies in our laboratory have demonstrated that an increase in intrathoracic temperature to slightly above 39 °C activated vagal pulmonary C-fiber endings in anesthetized rats. Similar stimulatory effect and temperature threshold for activation were also found in isolated vagal pulmonary sensory neurons. Results obtained from our present study performed in young mild asthmatic patients show: 1) Isocapnic hyperventilation (at ~40% of maximum voluntary ventilation) of humidified warm air for 4 min triggered bronchoconstriction and coughs in these patients. 2) Pretreatment with ipratropium bromide completely prevented the bronchoconstriction, but did not abolish the cough response. 3) In contrast, hyperventilation of humidified air at room temperature did not cause any significant change in airway resistance (Raw) or cough. 4) Airway hyperthermia failed to trigger any increase in Raw in healthy individuals. In conclusion, increasing airway temperature stimulated airway sensory nerves, presumably via an activation of TRPV1, and elicited cough and cholinergic reflex bronchoconstriction in mild asthmatic patients. These results suggest the possibility that either the thermal sensitivity or the expression of TRPV1 is upregulated in the airways of asthmatic patients.
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