Extracellular acidification attenuates bronchial contraction via an autocrine activation of EP receptor: Its diminishment in murine experimental asthma.

Purpose: Extracellular acidification is a major component of tissue inflammation, including airway inflammation in asthmatics. However, its physiological/pathophysiological significance in bronchial function is not fully understood. Currently, the functional role of extracellular acidification on bronchial contraction was explored.

Methods: Left main bronchi were isolated from male BALB/c mice. Epithelium-removed tissues were exposed to acidic pH under submaximal contraction induced by 10 M acetylcholine in the presence or absence of a COX inhibitor indomethacin (10 M). Effects of AH6809 (10 M, an EP receptor antagonist), BW A868C (10 M, a DP receptor antagonist) and CAY10441 (3×10 M, an IP receptor antagonist) on the acidification-induced change in tension were determined. The release of prostaglandin E (PGE) from epithelium-denuded tissues in response to acidic pH was assessed using an ELISA.

Results: In the bronchi stimulated with acetylcholine, change in the extracellular pH from 7.4 to 6.8 caused a transient augmentation of contraction followed by a sustained relaxing response. The latter inhibitory response was abolished by indomethacin and AH6809 but not by BW A868C or CAY10441. Both indomethacin and AH6809 significantly increased potency and efficacy of acetylcholine at pH 6.8. Stimulation with low pH caused an increase in PGE release from epithelium-denuded bronchi. Interestingly, the acidic pH-induced bronchial relaxation was significantly reduced in a murine asthma model that had a bronchial hyperresponsiveness to acetylcholine.

Conclusion: Taken together, extracellular acidification could inhibit the bronchial contraction via autocrine activation of EP receptors. The diminished acidic pH-mediated inhibition of bronchial tone may contribute to excessive bronchoconstriction in inflamed airways such as asthma.