Manoharan Palanikumar, Coon Steven, Baseler Walter, Sundaram Shanmuga, Kekuda Ramesh, Sundaram Uma
Section of Digestive Diseases and West Virginia Clinical and Translational Science Institute, West Virginia University, Morgantown, WV 26505, USA.
Biochim Biophys Acta. 2013 Feb;1828(2):179-86. doi: 10.1016/j.bbamem.2012.08.003. Epub 2012 Sep 3.
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.
先前的研究表明，在慢性肠道炎症期间，Cl(-)/HCO(3)(-)交换受到抑制，这是由于交换体对Cl(-)的亲和力降低而非转运体数量减少所致。花生四烯酸代谢产物（AAM）在慢性炎症小肠的黏膜中升高。然而，它们在慢性肠炎期间对Cl(-)/HCO(3)(-)改变中的作用尚不清楚。用花生四烯酰三氟甲基酮（ATMK）抑制慢性炎症兔肠道中的AAM形成，可逆转Cl(-)/HCO(3)(-)交换活性的降低。动力学研究表明，这种逆转是由于转运体改变的亲和力得以恢复。由于只有用吡罗昔康治疗抑制环氧化酶才能逆转被抑制的Cl(-)/HCO(3)(-)交换，因此确定AAM对Cl(-)/HCO(3)(-)抑制的下游调节是通过环氧化酶途径。此外，DRA被证明是绒毛细胞中主要的Cl(-)/HCO(3)(-)交换体。动力学和分子研究表明，环氧化酶途径代谢产物抑制Cl(-)/HCO(3)(-)交换的机制是由于转运体对Cl(-)的亲和力降低，而DRA刷状缘膜表达没有变化。因此，我们的数据表明，环氧化酶途径代谢产物在慢性肠道炎症期间介导了对DRA的抑制。
