Role of ATP in the ROS-mediated laryngeal airway hyperreactivity induced by laryngeal acid-pepsin insult in anesthetized rats.
The pathogenetic mechanisms of laryngeal airway hyperreactivity (LAH) in patients with extraesophageal reflux are unclear. We recently reported that a laryngeal acid-pepsin insult produces LAH that is mediated through sensitization of the capsaicin-sensitive laryngeal afferent fibers by reactive oxygen species (ROS) in rats. Since ROS may promote the release of ATP from cells, we hypothesized that activation of P2X purinoceptors by ATP subsequent to an increase in ROS induces LAH in an inflamed larynx that has been insulted by acid-pepsin or H(2)O(2) (a major type of ROS). The larynxes of 208 anesthetized rats were functionally isolated while the animals breathed spontaneously. Ammonia vapor was delivered into the larynx to measure laryngeal reflex reactivity. Laryngeal insult with acid-pepsin or H(2)O(2) produced LAH with similar characteristics. The H(2)O(2)-induced LAH was prevented by laryngeal pretreatment with dimethylthiourea (a hydroxyl radical scavenger), suggesting a critical role for ROS. The LAH induced by both insults were completely prevented by ATP scavengers (a combination of apyrase and adenosine deaminase) or a P2X receptor antagonist (iso-pyridoxalphosphate-6-azophenyl-2',5'-disulfonate). Laryngeal application of a P2X receptor agonist (alpha,beta-methylene-ATP) also produced LAH. An insult with either acid-pepsin or H(2)O(2) similarly promoted an increase in the levels of ATP, lipid peroxidation, and inflammation in the larynx. Our findings suggest that laryngeal insult with acid-pepsin or H(2)O(2) induces inflammation and produces excess ROS in the rat's larynx. The latter may in turn promote the release of ATP to activate P2X receptors, resulting in sensitization of capsaicin-sensitive laryngeal afferent fibers and LAH.
Tsai
Tung-Lung
TL
Institute of Physiology, School of Medicine, National Yang-Ming Univ., Taipei 11221, Taiwan.
Chang
Shyue-Yih
SY
Ho
Ching-Yin
CY
Kou
Yu Ru
YR
D000243:Adenosine Deaminase / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000502:physiology*; D000758:Anesthesia; D000818:Animals; D001081:Apyrase / Q000494:pharmacology; D004195:Disease Models, Animal; D004338:Drug Combinations; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007821:Laryngeal Muscles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D010434:Pepsin A / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology
D004338:Drug Combinations; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D010434:Pepsin A; D000243:Adenosine Deaminase; D001081:Apyrase