New therapeutic targets in ulcerative colitis: the importance of ion transporters in the human colon.

BACKGROUND: The absorption of water and ions (especially Na(+) and Cl(-)) is an important function of colonic epithelial cells in both physiological and pathophysiological conditions. Despite the comprehensive animal studies, there are only scarce available data on the ion transporter activities of the normal and inflamed human colon. METHODS: In this study, 128 healthy controls and 69 patients suffering from ulcerative colitis (UC) were involved. We investigated the expressional and functional characteristics of the Na(+)/H(+) exchangers (NHE) 1-3, the epithelial sodium channel (ENaC), and the SLC26A3 Cl(-)/HCO 3- exchanger downregulated in adenoma (DRA) in primary colonic crypts isolated from human biopsy and surgical samples using microfluorometry, patch clamp, and real-time reverse-transcription polymerase chain reaction (RT-PCR) techniques. RESULTS: Data collected from colonic crypts showed that the activities of electroneutral (via NHE3) and the electrogenic Na(+) absorption (via ENaC) are in inverse ratio to each other in the proximal and distal colon. We found no significant differences in the activity of NHE2 in different segments of the colon. Surface cell Cl(-)/HCO 3- exchange is more active in the distal part of the colon. Importantly, both sodium and chloride absorptions are damaged in UC, whereas NHE1, which has been shown to promote immune response, is upregulated by 6-fold. CONCLUSIONS: These results open up new therapeutic targets in UC.

Preserved Na(+)/H(+) exchanger isoform 3 expression and localization, but decreased NHE3 function indicate regulatory sodium transport defect in ulcerative colitis.

BACKGROUND: A major causative factor of diarrhea in ulcerative colitis (UC) patients is the loss of Na(+) absorptive capacity of the inflamed colonic mucosa. Potential contributing mechanisms include reduced driving force for active transport, and impaired expression, mislocalization, or defective transport function of Na(+) absorptive proteins. We therefore studied the expression, brush border membrane (BBM) localization, and transport capacity of the major intestinal Na(+) absorptive protein, the Na(+)/H(+) exchanger isoform 3 (NHE3) in biopsies from UC patients. METHODS: In UC and control biopsies, inflammation was graded histologically, NHE3, tumor necrosis factor alpha (TNF-alpha), villin, as well as other housekeeping genes were analyzed by quantitative real-time polymerase chain reaction (PCR), BBM localization of NHE3 determined by immunohistochemistry, and confocal microscopy. Na(+) absorptive capacity was assessed by (22)Na(+) isotope fluxes and NHE3 transport activity measured microfluorometrically in BCECF-loaded surface colonocytes within isolated crypts. RESULTS: In mildly, moderately, and severely inflamed sigmoid colon of UC patients, neither NHE3 mRNA expression nor the abundance of NHE3 in the BBM was significantly altered compared to other structural components of the BBM. However, Na(+) absorption was strongly reduced by approximately 80% and acid-activated NHE3 transport activity was significantly decreased in the surface cells of sigmoid colonic crypts even in moderately inflamed mucosa. CONCLUSIONS: In the colonic mucosa of patients with active UC, NHE3 transport capacity was found significantly decreased despite correct NHE3 location and abundance in the brush border, independent of current treatment. These findings suggest functional NHE3 transport as a novel factor for inflammatory diarrhea in UC patients.