Prostaglandins, not the leukotrienes, regulate Cl-/HCO 3- exchange (DRA, SLC26A3) in villus cells in the chronically inflamed rabbit ileum

摘要

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-/HCO3 - inhibition by AAM was determined to be by the cyclooxygenase pathway since only inhibition of cyclooxygenase with piroxicam treatment reversed the inhibited Cl -/HCO3 - exchange. Further, DRA was shown to be the primary Cl-/HCO3 - exchanger in villus cells. Kinetics and molecular studies indicated that the mechanism of inhibition of Cl-/HCO3 - 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.