Critical Roles for EGF Receptor Signaling During Resection‐Induced Intestinal Adaptation

Abstract

The adaptation response of the remnant gut to massive intestinal resection represents a mitogenic signal involving all bowel wall layers. In the mucosa, this response results in taller villi, deeper crypts, and enhanced enterocyte turnover as gauged by greater rates of both proliferation and apoptosis. Although the exact mechanisms and mediators of this important compensatory response remain incompletely understood, work from this laboratory over the past decade has illuminated a crucial role for intact receptor signaling for a robust response. Using a murine model for intestinal resection, transgenic, null and mutant mouse strains have provided unique experimental paradigms to dissect molecular mechanisms for epidermal growth factor (EGF) receptor-directed influence on adaptation. Stimulation of this receptor is linked with a magnified adaptation response, whereas attenuation of the activity of this receptor is associated with impaired adaptation. EGF receptor activation and expression are both elevated in enterocytes after resection, and salivary levels of EGF-the major ligand for the EGF receptor-are increased. In addition to stimulation of enterocyte proliferation, EGF receptor signaling prevents the typical increase in rates of enterocyte apoptosis, probably by affecting the ratio of expression of both pro- and anti-apoptotic Bcl-2 family members. The key to optimizing care for patients with short gut syndrome will necessarily follow a thorough understanding of intestinal adaptation responses.

New Therapies and Preventive Approaches for Necrotizing Enterocolitis: Report of a Research Planning Workshop

“…Exogenous EGF has been shown to enhance RIA in mouse models, causing increases in intestine length, villus height, and crypt depth. EGF stimulates enterocyte proliferation and limits apoptosis, tipping enterocyte homeostasis toward enhanced proliferation to facilitate mucosal growth (5). EGF also may be involved in the smooth muscle cell proliferation required for the bowel lengthening and the increase in intestinal circumference that occurs during RIA.…”

Epidermal growth factor receptor signaling modulates apoptosis via p38α MAPK-dependent activation of Bax in intestinal epithelial cells

“…Over the past decade, our laboratory has illuminated a central role for EGFR signaling in the genesis of resection-induced adaptation (26). In addition to affecting rates of enterocyte proliferation, EGFR activity was also found to regulate enterocyte apoptosis after massive small bowel resection (SBR) (14,18).…”

Hydrocortisone and Indomethacin Negatively Modulate EGF-R Signaling in Human Fetal Intestine

“…In accordance with the proliferative effect of EGF in FHs74Int cells, EGF-R activation enhances recovery from small bowel resection (SBR) (28). Adaptation of the premature gut to extrauterine conditions mimics SBR, i.e.…”

“…Adaptation of the premature gut to extrauterine conditions mimics SBR, i.e. development of taller villi, deeper crypts and enhanced enterocyte turnover (28). Moreover, problems seen with preterm infants resemble animal models of insufficient EGF-R signaling, i.e.…”

“…Interestingly, dexamethasone treatment leads to down-regulated EGF-R and TGF-␣ expression in muscularis mucosae and thinning of the ileal wall (27). EGF-R signaling, on the other hand, seems to be important for intestinal wall and adaptation processes since EGF-R transcription is up-regulated in smooth muscle layer after bowel resection (28). Taken together, combination of prostaglandin inhibition, glucocorticoid treatment, and insufficient EGF-R signaling could be detrimental to intestinal wall leading to perforations.…”