Department of Clinical and Translational Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA.
Int J Mol Sci. 2021 Apr 17;22(8):4171. doi: 10.3390/ijms22084171.
Electrolytes (NaCl) and fluid malabsorption cause diarrhea in inflammatory bowel disease (IBD). Coupled NaCl absorption, mediated by Na/H and Cl/HCO exchanges on the intestinal villus cells brush border membrane (BBM), is inhibited in IBD. Arachidonic acid metabolites (AAMs) formed via cyclooxygenase (COX) or lipoxygenase (LOX) pathways are elevated in IBD. However, their effects on NaCl absorption are not known. We treated SAMP1/YitFc (SAMP1) mice, a model of spontaneous ileitis resembling human IBD, with Arachidonyl Trifluoro Methylketone (ATMK, AAM inhibitor), or with piroxicam or MK-886, to inhibit COX or LOX pathways, respectively. Cl/HCO exchange, measured as DIDS-sensitive Cl uptake, was significantly inhibited in villus cells and BBM vesicles of SAMP1 mice compared to AKR/J controls, an effect reversed by ATMK. Piroxicam, but not MK-886, also reversed the inhibition. Kinetic studies showed that inhibition was secondary to altered K with no effects on V. Whole cell or BBM protein levels of Down-Regulated in Adenoma (SLC26A3) and putative anion transporter-1 (SLC26A6), the two key BBM Cl/HCO exchangers, were unaltered. Thus, inhibition of villus cell Cl/HCO exchange by COX pathway AAMs, such as prostaglandins, via reducing the affinity of the exchanger for Cl, and thereby causing NaCl malabsorption, could significantly contribute to IBD-associated diarrhea.
电解质（NaCl）和液体吸收不良会导致炎症性肠病（IBD）腹泻。肠绒毛细胞刷状缘膜（BBM）上的 Na/H 和 Cl/HCO 交换介导的耦合 NaCl 吸收在 IBD 中受到抑制。环氧化酶（COX）或脂氧合酶（LOX）途径形成的花生四烯酸代谢物（AAMs）在 IBD 中升高。然而，它们对 NaCl 吸收的影响尚不清楚。我们用 Arachidonyl Trifluoro Methylketone（ATMK，AAM 抑制剂）或吡罗昔康或 MK-886 治疗 SAMP1/YitFc（SAMP1）小鼠，一种类似于人类 IBD 的自发性回肠炎模型，分别抑制 COX 或 LOX 途径。与 AKR/J 对照相比，SAMP1 小鼠的绒毛细胞和 BBM 囊泡中的 Cl/HCO 交换（以 DIDS 敏感的 Cl 摄取衡量）显著受到抑制，这种抑制作用被 ATMK 逆转。吡罗昔康，但不是 MK-886，也逆转了抑制作用。动力学研究表明，抑制作用继发于 K 的改变，对 V 没有影响。腺瘤下调（SLC26A3）和假定阴离子转运蛋白-1（SLC26A6）的全细胞或 BBM 蛋白水平，这两种关键的 BBM Cl/HCO 交换器，均未改变。因此，COX 途径 AAMs（如前列腺素）通过降低交换器对 Cl 的亲和力来抑制绒毛细胞 Cl/HCO 交换，从而导致 NaCl 吸收不良，这可能会显著导致 IBD 相关腹泻。
