E-Ring Isoprostanes Stimulate a Cl Conductance in Airway Epithelium via Prostaglandin E2-Selective Prostanoid Receptors.
Isoprostanes comprise a class of membrane lipid metabolites produced during oxidative stress, including asthma, chronic obstructive pulmonary disease, and cystic fibrosis. They are widely recognized to evoke a variety of biological responses in airway and pulmonary vascular smooth muscle, lymphatics, and innervation. However, their effects on airway epithelium are largely unstudied. We examined the electrophysiological responses evoked by several different isoprostane species in bovine airway epithelium using the Ussing chamber technique. The E-ring isoprostanes 15-E(1t)-IsoP and 15-E(2t)-IsoP evoked a substantial increase in short-circuit current (I(SC)), whereas four different F-ring isomers were ineffective. 15-E(2t)-IsoP-evoked I(SC) was mimicked by the prostaglandin E(2)-selective prostanoid receptor (EP)-agonist prostaglandin E(2) but not by agonists of EP(1)/EP(3)-, FP-, or TP receptors (sulprostone, fluprostenol, and U46619, respectively). This response was significantly reduced by the EP(4)-receptor blocker GW627386 but not by blockers of other prostanoid receptors (ICI 192,605 [TP-selective], SC19220 [EP(1)-selective], AH6809 [DP/EP(1)/EP(2)-selective], and AL8810 [FP-selective]). 15-E(2t)-IsoP-evoked I(SC) was reduced by blockers of Cl(-) channels (niflumic acid and 5-nitro-2-(3-phenylpropylamino)-benzoic acid), of Na(+)/K(+)/2Cl(-) co-transport (furosemide and bumetanide), of adenylate cyclase (MDL 12,330A), or of guanylate cyclase (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) but not by blockers of Na(+) conductances (amiloride). We conclude that 15-E(2t)-IsoP activates a transepithelial Cl(-) conductance in bovine airway epithelium through an EP(4) receptor coupled to adenylate cyclase and soluble guanylate cyclase.
Firestone Institute for Respiratory Health, St. Joseph's Healthcare, and Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Victoria
V
Seto
Christina
C
Hirota
Simon
S
Hirota
Luke J
LJ
Janssen
D000818:Animals; D002417:Cattle; D065101:Chloride Channel Agonists; D018118:Chloride Channels / Q000378:metabolism*; D004553:Electric Conductivity; D005071:Evoked Potentials / Q000187:drug effects; D017136:Ion Transport / Q000187:drug effects; D028421:Isoprostanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008563:Membrane Lipids / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000294:innervation / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D020545:Respiratory Mucosa / Q000294:innervation / Q000378:metabolism* / Q000473:pathology; D046509:Tissue Culture Techniques; D014132:Trachea / Q000294:innervation / Q000378:metabolism* / Q000473:pathology
D065101:Chloride Channel Agonists; D018118:Chloride Channels; D028421:Isoprostanes; D008563:Membrane Lipids; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype