Early Epithelial Restitution by Nonsteroidal Anti-Inflammatory Drug-Activated Gene 1 Counteracts Intestinal Ulcerative Injuries

In response to ulcerative mucosal injuries, intestinal epithelial restitution is a critical event in the early defense against harmful attacks by luminal Ags. Based on the assumption that epithelial NAG-1 is an endogenous regulator of ulcerative stress-induced injuries, the expression and functions of NAG-1 were investigated. Genetic ablation of NAG-1 decreased survival of mice with dextran sodium sulfate-induced intestinal ulcer and histologically delayed the epithelial restitution, confirming early protective roles of NAG-1 in ulcerative insults. Moreover, enhanced expression of NAG-1 during the wound-healing process was associated with epithelial cell migration and spreading. In response to ulcerative injury, RhoA GTPase, a cytoskeleton modulator, mediated epithelial restitution via enhanced motility. RhoA expression was prominently elevated in the restituting epithelia cells around the insulted wound bed and was attenuated by NAG-1 deficiency. Pharmacological intervention with RhoA thus attenuated NAG-1-mediated epithelial cell migration during epithelial restitution. Taken together, epithelial restitution was promoted by enhanced NAG-1 expression and subsequent enterocyte locomotion during the early wound-healing process, suggesting clinical usefulness of NAG-1 as a novel endogenous muco-protective factor or an indicator of therapeutic efficacy against the ulcerative gastrointestinal diseases, including inflammatory bowel disease.