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

Abstract

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.

HuR Enhances Early Restitution of the Intestinal Epithelium by Increasing Cdc42 Translation

“…In stressful environments, successful repair of wounds and ulcers requires epithelial cells to rapidly change gene expression patterns to regulate cell survival, migration, proliferation, and differentiation (2,3). Early epithelial restitution is a primary repair modality in the gastrointestinal tract, and it rapidly reseals superficial wounds by migrating visible remaining epithelial cells from areas adjacent to the injured surface to cover the wounded area, followed by proliferation and differentiation (4,5). This early rapid mucosal reepithelialization after mucosal injury is a complex process that includes the flattening, spreading, migrating, and repolarizing of differentiated columnar epithelial cells but is independent of cell proliferation (2,6).…”

Mucosal ribosomal stress-induced PRDM1 promotes chemoresistance via stemness regulation

“…All procedures are based on the previous reports 57 – 59 . Tumor samples were dehydrated, embedded in paraffin, and cut into 5 μm sections for immunohistochemistry (IHC) analysis.…”

Nononcogenic restoration of the intestinal barrier by E. coli–delivered human EGF

“…H&E staining was performed using standard procedures. Scoring of disease severity was based on the following 4 parameters as described in a previous report (57). Severity of inflammation was scored as follows: 0, rare inflammatory cells in the lamina propria; 1, increased numbers of granulocytes in the lamina propria; 2, confluence of inflammatory cells extending into the submucosa; 3, transmural extension of the inflammatory infiltrate.…”

“…All samples were centrifuged at 140 g for 15 minutes at 4°C, after which the supernatant was collected. The process of Western blot analysis was described previously (57).…”