M. Nguyen1, O. Escobar1, C. Gayer1 1Children’s Hospital Los Angeles,Pediatric Surgery,Los Angeles, CALIFORNIA, USA
Introduction:
Ursodeoxycholic acid (UDCA) is a secondary bile acid that, unlike many other bile acids, is hydrophilic and has anti-inflammatory properties. We have previously demonstrated that UDCA inhibits intestinal epithelial cell proliferation and stimulates migration in in vitro through an EGFR-dependent mechanism involving downstream COX-2 upregulation. We hypothesize that UDCA will protect the intestinal epithelial barrier in an acute model of intestinal injury via a pathway that requires EGFR, ERK, and COX-2.
Methods:
Wild-type C57BL/6 or Velvet (EGFR dominant-negative) mice underwent intraperitoneal injections of 30 mg/kg lipopolysaccharide (LPS) and oral gavage of 175 mg/kg fluorescein isothiocyanate (FITC)-dextran, with or without 100 mg/kg UDCA . Mice were sacrificed at 16 hours, and small intestine and serum were harvested. Phosphorylated ERK and COX-2 were measured by Western blot and immunofluorescent (IF) staining of intestine. FITC-dextran levels were measured by fluorimetry of serum.
Results:
Mice treated with UDCA demonstrated decreased villus height loss and serum FITC-dextran levels, as previously reported. Western blot revealed that small intestine mucosal scrapings of these same mice contained increased phosphorylated ERK. This effect was attenuated in mice treated with UDCA + LPS, and further attenuated in mice treated with LPS alone. As expected, small intestine mucosal scrapings of mice treated with LPS alone contained increased COX-2. Conversely, COX-2 was decreased in mice treated with UDCA and further decreased in mice treated with UDCA + LPS, though the differences were very slight. IF staining demonstrated increased COX-2 expression in mice treated with UDCA + LPS, though there was no appreciable difference in COX-2 expression among mice undergoing other treatments.
Conclusion:
These data suggest that UDCA protects the intestinal epithelial barrier in part through an EGFR- and ERK-dependent mechanism. In the context of our previously reported in vitro data showing that UDCA increases intestinal epithelial cell migration through a mechanism dependent on EGFR, COX-2, and ERK, the data presented here further support that UDCA could be used to protect the intestine from acute injury.