The prostaglandin E₂ type 4 receptor participates in the response to acute oxidant stress in airway epithelial cells.

Christina L Jones, Tiesong Li, Elizabeth A Cowley

Index: J. Pharmacol. Exp. Ther. 341(2) , 552-63, (2012)

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Abstract

Oxidative stress is implicated in the pathogenesis of many inflammatory pulmonary diseases, including cystic fibrosis (CF). Delineating how oxidative stress stimulates CF transmembrane conductance regulator (CFTR) in airway epithelial cells is useful, both to increase the understanding of airways host defense and suggest therapeutic approaches to reduce the oxidant stress burden in the CF lung. Using the airway epithelial cell line Calu-3, we investigated the hypothesis that hydrogen peroxide (H₂O₂), which stimulates anion efflux through CFTR, does so via the production of prostaglandin E₂ (PGE₂). Using iodide efflux as a biochemical marker of CFTR activity and short circuit current (I(sc)) recordings, we found that the H₂O₂-stimulated efflux was abolished by cyclooxygenase-1 inhibition and potentially also involves microsomal prostaglandin E synthase-1 activity, implicating a role for PGE₂ production. Furthermore, H₂O₂ application resulted in a rapid release of PGE₂ from Calu-3 cells. We additionally hypothesized that the PGE₂ subtype 4 (EP(4)) receptor was involved in mediating this response. In the presence of (4Z)-7-[(rel-1S,2S,5R)-5-((1,1'-biphenyl-4-yl)methoxy)-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid (AH23848) (which blocks the EP₄ receptor), the H₂O₂-stimulated response was abolished. To investigate this finding in a polarized system, we measured the increase in I(sc) induced by H₂O₂ addition in the presence and absence of AH23848. H₂O₂ induced a robust increase in I(sc), which was significantly attenuated in the presence of AH23848, suggesting some role for the EP₄ receptor. In conclusion, with H₂O₂ as a model oxidant stress, stimulation of CFTR seems to involve PGE₂ production and likely EP₄ receptor activation in Calu-3 airway epithelial cells. This mechanism would be compromised in the CF airways.