Prostaglandin E2-induced colonic secretion in patients with and without colorectal neoplasia

Abstract

BackgroundThe pathogenesis for colorectal cancer remains unresolved. A growing body of evidence suggests a direct correlation between cyclooxygenase enzyme expression, prostaglandin E2 metabolism and neoplastic development. Thus further understanding of the regulation of epithelial functions by prostaglandin E2 is needed. We hypothesized that patients with colonic neoplasia have altered colonic epithelial ion transport and express functionally different prostanoid receptor levels in this respect.MethodsPatients referred for colonoscopy were included and grouped into patients with and without colorectal neoplasia. Patients without endoscopic findings of neoplasia served as controls. Biopsy specimens were obtained from normally appearing mucosa in the sigmoid part of colon. Biopsies were mounted in miniaturized modified Ussing air-suction chambers. Indomethacin (10 μM), various stimulators and inhibitors of prostanoid receptors and ion transport were subsequently added to the chamber solutions. Electrogenic ion transport parameters (short circuit current and slope conductance) were recorded. Tissue pathology and tissue damage before and after experiments was assessed by histology.ResultsBaseline short circuit current and slope conductance did not differ between the two groups. Patients with neoplasia were significantly more sensitive to indomethacin with a decrease in short circuit current of 15.1 ± 2.6 μA·cm-2 compared to controls, who showed a decrease of 10.5 ± 2.1 μA·cm-2 (p = 0.027). Stimulation or inhibition with theophylline, ouabain, bumetanide, forskolin or the EP receptor agonists prostaglandin E2, butaprost, sulprostone and prostaglandin E1 (OH) did not differ significantly between the two groups. Histology was with normal findings in both groups.ConclusionsEpithelial electrogenic transport is more sensitive to indomethacin in normal colonic mucosa from patients with previous or present colorectal neoplasia compared to colonic mucosa from control patients. Stimulated epithelial electrogenic transport through individual prostanoid subtype receptors EP1, EP2, EP3, and EP4 is not significantly different between neoplasia diseased patients and controls. This indicates that increased indomethacin-sensitive mechanisms in colonic mucosa from neoplasia diseased patients are not related to differences in functional expression of EP receptor subtypes.

Phosphodiesterases in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia

“…The method used has previously been described in detail [21, 22]. Correction for media resistance between tips of potential electrodes was carried out just before mounting of biopsies, thus circumventing challenges of edge damage in measuring correct active ion transport.…”

PGE2 is a direct and robust mediator of anion/fluid secretion by human intestinal epithelial cells

“…The function of PGE 2 is highly pleiotropic, as it can regulate the secretion of anions17 and mucus18, GI motility19, and the survival and proliferation of IECs2021. PGE 2 may also contribute to the maintenance of the stem-like properties of IECs through the enhancement of Wnt signalling2223. In addition, PGE 2 is one of the inflammatory mediators upregulated in inflammatory bowel disease (IBD)2425.…”

Lubiprostone for the Treatment of Adults with Constipation and Irritable Bowel Syndrome

“…Lubiprostone does not enhance colonic motor activity, and is unlikely to cause accelerated colonic transit, although may facilitate laxation through its secretory effect [55,57]. A previous study had demonstrated that lubiprostone retarded gastric emptying compared to a placebo, but it accelerated small-bowel and colonic transit time in healthy subjects [29].…”