Unique Regulation of Intestinal Villus Epithelial Cl-/HCO3- Exchange by Cyclooxygenase Pathway Metabolites of Arachidonic Acid in a Mouse Model of Spontaneous Ileitis.

M Motiur Rahman,Uma Sundaram,Sheuli Afroz,Alip Borthakur,Subha Arthur

doi:10.3390/ijms22084171

M Motiur Rahman, Uma Sundaram + Show 3 more

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https://doi.org/10.3390/ijms22084171

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Abstract

Electrolytes (NaCl) and fluid malabsorption cause diarrhea in inflammatory bowel disease (IBD). Coupled NaCl absorption, mediated by Na+/H+ and Cl−/HCO3− 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−/HCO3− exchange, measured as DIDS-sensitive 36Cl 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 Km with no effects on Vmax. Whole cell or BBM protein levels of Down-Regulated in Adenoma (SLC26A3) and putative anion transporter-1 (SLC26A6), the two key BBM Cl−/HCO3− exchangers, were unaltered. Thus, inhibition of villus cell Cl−/HCO3− 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.

Highlights

Histologic results indicate that SAMP1 mice spontaneously develop lesions in their terminal ilea, reminiscent of human inflammatory bowel disease (IBD), and in vivo treatment of SAMP1 mice with a COX pathway inhibitor has no effects on ileal structure
Our results demonstrated significant inhibition of Cl−/HCO3− exchange, a component of coupled normal fluid and electrolyte (NaCl) absorption in the brush border membrane (BBM) of intestinal villus cells in chronic inflammation
Extensive studies focused on the molecular pathophysiology of IBD-associated diarrhea, suggest that impaired NaCl absorption, rather than anion secretion, primarily contributes to diarrhea in IBD [10]

Summary

Introduction

IBD affects more than 3.5 million people in the United States and Europe, with a steep increase in incidence over the past 50 years [4,5]. The etiology of IBD is complex, there is no cure, and the cause of the disease remains unclear, limiting the development of therapeutic strategy to prevent its occurrence. The most common and disabling morbidity of human IBD, is prevalent in almost 80% of the patients [6]. IBD-associated diarrhea is multifactorial and appears to be the outcome of intricate pathophysiological events arising from widespread and sustained mucosal inflammation [6]. Akin to all diarrheal diseases, decreased absorption, increased secretion, or both, of fluid and electrolyte is a common manifestation of IBD-associated diarrhea [7,8,9]

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