title: Prostaglandins, not the leukotrienes, regulate Cl(-)/HCO(3)(-) exchange (DRA, SLC26A3) in villus cells in the chronically inflamed rabbit ileum.
abstract: Previously studies have demonstrated that Cl(-)/HCO(3)(-) exchange was inhibited during chronic intestinal inflammation secondary to decrease in the affinity of the exchanger for Cl(-) rather than the number of transporters. Arachidonic acid metabolites (AAM) are elevated in the mucosa of the chronically inflamed small intestine. However, their role in the alteration of Cl(-)/HCO(3)(-) during chronic enteritis was unknown. Inhibition of AAM formation with arachidonyl trifluoro methylketone (ATMK) in chronically inflamed rabbit intestine reversed the diminished Cl(-)/HCO(3)(-) exchange activity. Kinetics studies showed that the reversal was secondary to restoration of the altered affinity of transporter. Downstream regulation of Cl(-)/HCO(3)(-) inhibition by AAM was determined to be by the cyclooxygenase pathway since only inhibition of cyclooxygenase with piroxicam treatment reversed the inhibited Cl(-)/HCO(3)(-) exchange. Further, DRA was shown to be the primary Cl(-)/HCO(3)(-) exchanger in villus cells. Kinetics and molecular studies indicated that the mechanism of inhibition of Cl(-)/HCO(3)(-) exchange by cyclooxygenase pathway metabolites was secondary to diminished affinity of the transporter for Cl(-) without a change in DRA BBM expression. Thus our data indicated that cyclooxygenase pathway metabolites mediate the inhibition of DRA during chronic intestinal inflammation.
authors.affiliation: Section of Digestive Diseases and West Virginia Clinical and Translational Science Institute, West Virginia University, Morgantown, WV 26505, USA.
authors.forename: Palanikumar
authors.initials: P
authors.lastname: Manoharan
authors.forename: Steven
authors.initials: S
authors.lastname: Coon
authors.forename: Walter
authors.initials: W
authors.lastname: Baseler
authors.forename: Shanmuga
authors.initials: S
authors.lastname: Sundaram
authors.forename: Ramesh
authors.initials: R
authors.lastname: Kekuda
authors.forename: Uma
authors.initials: U
authors.lastname: Sundaram
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D027963:Chloride-Bicarbonate Antiporters / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007082:Ileum / Q000378:metabolism*; D007150:Immunohistochemistry / Q000379:methods; D007211:Indoles / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007659:Ketones / Q000378:metabolism; D007700:Kinetics; D015289:Leukotrienes / Q000378:metabolism*; D008297:Male; D008871:Microvilli / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism*; D011817:Rabbits; D002722:Chlorobenzenes
chemical_list: D016718:Arachidonic Acid; D027963:Chloride-Bicarbonate Antiporters; D007211:Indoles; D007659:Ketones; D015289:Leukotrienes; D011453:Prostaglandins; C060893:MK-886; D002722:Chlorobenzenes