Osmotic regulation of airway reactivity by epithelium

Inhalation of nonisotonic solutions can elicit pulmonary obstruction in ast hmatic airways. We evaluated the hypothesis that the respiratory epithelium is involved in responses of the airways to nonisotonic solutions using the guinea pig isolated, perfused trachea preparation to restrict applied agen ts to the mucosal (intraluminal) or serosal (extraluminal) surface of the a irway. In methacholine-contracted tracheae, intraluminally applied NaCl or KCl equipotently caused relaxation that was unaffected by the cyclo-oxygena se inhibitor, indomethacin, but was attenuated by removal of the epithelium and Na+ and Cl- channel blockers. Na+-K+-2Cl(-) cotransporter and nitric o xide synthase blockers caused a slight inhibition of relaxation, whereas Na +,K+-pump inhibition produced a small potentiation. Intraluminal hyperosmol ar KCl and Nacl inhibited contractions in response to intra- or extralumina lly applied methacholine, as well as neurogenic cholinergic contractions el icited with electric field stimulation (+/- indomethacin). Extraluminally a pplied NaCl and KCl elicited epithelium-dependent relaxation (which for KCl was followed by contraction). In contrast to the effects of hyperosmolarit y, intratuminal hypo-osmolarity caused papaverine-inhibitable contractions (+/- epithelium). These findings suggest that the epithelium is an osmotic sensor which, through the release of epithelium-derived relaxing factor, ca n regulate airway diameter by modulating smooth muscle responsiveness and e xcitatory neurotransmission.