Lubiprostone reduces murine colitis principally in a ClC‐2‐dependent manner. (LB750)

Abstract

Lubiprostone, a ClC‐2 chloride channel activator, induces intestinal secretion and is used in the management of idiopathic chronic constipation. Recent studies have suggested that lubiprostone has multiple targets and mechanisms of action in the intestine. However, we have previously reported that lubiprostone initiates intestinal barrier repair in ischemic‐injured intestine via its principal target, the chloride channel ClC‐2. Thus, we hypothesized that lubiprostone would have a protective or therapeutic effect in an in vivo colitis model. We administrated lubiprostone in a dextran sulfate sodium (DSS)‐induced colitis model in wild type and ClC‐2‐/‐ mice. We determined the severity of colitis based on body weight, disease activity index (DAI), histology scores, and levels of cytokine production. Additionally, intestinal permeability was measured in vivo to evaluate barrier function. Administration of DSS in the drinking water initiated symptoms of experimental IBD, including weight loos and elevation in DAI. Oral preventive or therapeutic administration of lubiprostone significantly reduced weight loss, DAI, histology scores, colon shortening, and intestinal permeability in a dose‐dependent manner as compared to DSS‐treated wild type mice that were not treated with lubiprostone. We also observed that the lubiprostone caused a significant elevation of the sealing tight junction protein expression for occludin and claudin‐1, while significant reduction of the pore‐forming tight junction protein claudin‐2. When administered to ClC‐2‐/‐ mice, the oral preventive lubiprostone treatment had a limited protective effect against DSS colitis. Specifically, loss of body weight, DAI, and intestinal permeability were significantly reduced in the high dose (100 μg/kg) lubiprostone treatment group of ClC‐2‐/‐ mice, but they showed no difference in colon length and histology score. In conclusion, lubiprostone might possess potential therapeutic interest for the treatment of IBD in a ClC‐2 dependent, but it also has some alternative mechanisms of action at high dosages. Additional investigation is required to determine the detailed mechanisms of action of lubiprostone in experimental colitis model.Grant Funding Source: Supported by Sucampo Pharmaceuticals inc. and Takeda Pharmaceuticals inc