Ursodeoxycholic acid protects against intestinal barrier breakdown by promoting enterocyte migration via EGFR- and COX-2-dependent mechanisms

摘要

The intestinal barrier is often disrupted in disease states, and intestinal barrier failure leads to sepsis. Ursodeoxycholic acid (LJDCA) is a bile acid that may protect the intestinal barrier. We hypothesized that LJDCA would protect the intestinal epithelium in injury models. To test this hypothesis, we utilized an in vitro wound-healing assay and a mouse model of intestinal barrier injury. We found that LJDCA stimulates intestinal epithelial cell migration in vitro, and this migration was blocked by inhibition of cyclooxygenase 2 (COX-2), epidermal growth factor receptor (EGFR), or ERK. Furthermore, LJDCA stimulated both COX-2 induction and EGFR phosphorylation. In vivo LJDCA protected the intestinal barrier from LPS-induced injury as measured by FITC dextran leakage into the serum. Using 5-bromo-2'-deoxyuridine and 5-ethynyl-2'-deoxyuridine injections, we found that LJDCA stimulated intestinal epithelial cell migration in these animals. These effects were blocked with cither administration of Rofecoxib, a COX-2 inhibitor, or in EGFR-dominant negative Velvet mice, wherein LJDCA had no effect on LPS-induced injury.