Lubiprostone prevents nonsteroidal anti-inflammatory drug-induced small intestinal damage by suppressing the expression of inflammatory mediators via EP4 receptors.

Lubiprostone, a bicyclic fatty acid derived from prostaglandin E1, has been used to treat chronic constipation and irritable bowel syndrome, and its mechanism of action has been attributed to the stimulation of intestinal fluid secretion via the activation of the chloride channel protein 2/cystic fibrosis transmembrane regulator (ClC-2/CFTR) chloride channels. We examined the effects of lubiprostone on indomethacin-induced enteropathy and investigated the functional mechanisms involved, including its relationship with the EP4 receptor subtype. Male Sprague-Dawley rats were administered indomethacin (10 mg/kg p.o.) and killed 24 hours later to examine the hemorrhagic lesions that developed in the small intestine. Lubiprostone (0.01-1 mg/kg) was administered orally twice 30 minutes before and 9 h after the indomethacin treatment. Indomethacin markedly damaged the small intestine, accompanied by intestinal hypermotility, a decrease in mucus and fluid secretion, and an increase in enterobacterial invasion as well as the up-regulation of inducible nitric-oxide synthase (iNOS) and tumor necrosis factor α (TNFα) mRNAs. Lubiprostone significantly reduced the severity of these lesions, with the concomitant suppression of the functional changes. The effects of lubiprostone on the intestinal lesions and functional alterations were significantly abrogated by the coadministration of AE3-208 [4-(4-cyano-2-(2-(4-fluoronaphthalen-1-yl)propionylamino)phenyl)butyric acid], a selective EP4 antagonist, but not by CFTR(inh)-172, a CFTR inhibitor. These results suggest that lubiprostone may prevent indomethacin-induced enteropathy via an EP4 receptor-dependent mechanism. This effect may be functionally associated with the inhibition of intestinal hypermotility and increase in mucus/fluid secretion, resulting in the suppression of bacterial invasion and iNOS/TNFα expression, which are major pathogenic events in enteropathy. The direct activation of CFTR/ClC-2 chloride channels is not likely to have contributed to the protective effects of lubiprostone.

Involvement of aquaporin-1 in gastric epithelial cell migration during wound repair.

We examined the expression of aquaporin (AQP)-1 in monolayers of the rat gastric epithelial cell line RGM1 and investigated the roles AQP1 plays in the epithelial restitution during wound healing. A round wound of constant size was produced in the center of a confluent cell monolayer using a rotating silicon tip. The RGM1 cells expressed AQP1 mRNA. Hg(2+) (HgCl(2)), an inhibitor of AQPs, suppressed cell migration during wound repair in a concentration-dependent manner. Likewise, cell migration was also impaired in cells in which AQP1 was knocked down by RNA interference, resulting in a marked delay of wound healing. The AQP1 knockdown RGM1 cells showed a decrease in the formation of membrane protrusions (lamellipodia) at the leading edge of the wound as compared with control RGM1 cells. These results suggest for the first time that AQP1 plays a crucial role in gastric epithelial cell migration during wound healing.