Neural and hydroxyl radical mechanisms underlying laryngeal airway hyperreactivity induced by laryngeal acid-pepsin insult in anesthetized rats

J Appl Physiol (1985). 2006 Jul;101(1):328-38. doi: 10.1152/japplphysiol.00064.2006.


Laryngopharyngeal or gastroesophageal reflux is associated with laryngeal airway hyperreactivity (LAH), but neither the cause-effect relationship nor the underlying mechanism has been elucidated. Here we established a rat model with enhanced laryngeal reflex reactivity induced by laryngeal acid-pepsin insult and investigated the neural and hydroxyl radical (*OH) mechanisms involved. The laryngeal segments of 103 anesthetized rats were functionally isolated while animals breathed spontaneously. Ammonia vapor was delivered into the laryngeal segment to measure laryngeal reflex reactivity. We found that the laryngeal pH 5-pepsin treatment doubled the reflex apneic response to ammonia, whereas laryngeal pH 7.4-pepsin, pH 2-pepsin, and pH 5-denatured pepsin treatment had no effect. Histological examination revealed limited laryngeal inflammation and epithelial damage after pH 5-pepsin treatment and more severe damage after pH 2-pepsin treatment. In rats that had received the laryngeal pH 5-pepsin treatment, the apneic response to ammonia was abolished by either denervation or perineural capsaicin treatment (PCT; a procedure that selectively blocks capsaicin-sensitive afferent fibers) of the superior laryngeal nerves, but was unaffected by perineural sham treatment. LAH was prevented by laryngeal application of either dimethylthiourea (DMTU; a *OH scavenger) or deferoxamine (DEF; an antioxidant for *OH), but was unaltered by the DMTU vehicle or iron-saturated DEF (ineffective DEF). LAH reappeared after recovery from PCT, DMTU, or DEF treatment. We conclude that 1) laryngeal insult by pepsin at a weakly acidic pH, but not at acidic pH, can produce LAH; and 2) LAH is probably mediated through sensitization of the capsaicin-sensitive laryngeal afferent fibers by a *OH mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology
  • Ammonia
  • Animals
  • Antioxidants / pharmacology
  • Blood Pressure / physiology
  • Capsaicin / pharmacology
  • Deferoxamine / pharmacology
  • Electrophysiology
  • Free Radical Scavengers / pharmacology
  • Gastroesophageal Reflux / physiopathology
  • Hydrogen-Ion Concentration
  • Hydroxyl Radical / analysis
  • Hydroxyl Radical / pharmacology*
  • Inflammation / etiology
  • Inflammation / pathology
  • Inflammation / physiopathology
  • Laryngeal Muscles / drug effects*
  • Laryngeal Muscles / innervation
  • Laryngeal Muscles / pathology
  • Laryngeal Muscles / physiology*
  • Male
  • Neurons, Afferent / drug effects
  • Neurons, Afferent / physiology*
  • Pepsin A / adverse effects
  • Pepsin A / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Respiratory Hypersensitivity / chemically induced*
  • Respiratory Hypersensitivity / pathology
  • Respiratory Hypersensitivity / physiopathology*
  • Thiourea / analogs & derivatives
  • Thiourea / pharmacology


  • Antioxidants
  • Free Radical Scavengers
  • Hydroxyl Radical
  • Ammonia
  • 1,3-dimethylthiourea
  • Pepsin A
  • Thiourea
  • Deferoxamine
  • Capsaicin