Selective Inhibition of the Epidermal Growth Factor Receptor Impairs Intestinal Adaptation after Small Bowel Resection

• Published in: The Journal of surgical research 2002-06, Vol.105 (1), p.25-30
• Main Authors: O'Brien, David P., Nelson, Lindsey A., Williams, Jodi L., Kemp, Christopher J., Erwin, Christopher R., Warner, Brad W.
• Format: Article
• Language: English
• Subjects: Adaptation, Physiological - drug effects; Adaptation, Physiological - physiology; Animals; Apoptosis - drug effects; Biological and medical sciences; Enterocytes - cytology; Enterocytes - physiology; Enzyme Inhibitors - pharmacology; epidermal growth factor receptor; intestinal adaptation; Intestine, Small - cytology; Intestine, Small - physiology; Intestine, Small - surgery; Male; Medical sciences; Mice; Mice, Inbred ICR; Quinazolines - pharmacology; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - physiology; short bowel syndrome; Short Bowel Syndrome - physiopathology; Signal Transduction - physiology; Stomach, duodenum, intestine, rectum, anus; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the digestive system
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1006/jsre.2002.6440

Background. Prior indirect studies have suggested that a functional epidermal growth factor receptor (EGFR) appears to be indispensable for the adaptive response of the remnant intestine to massive small bowel resection (SBR). The recent availability of a specific pharmacologic EGFR inhibitor enabled us to more directly test the hypothesis that EGFR signaling is required for postresection intestinal adaptation. Methods. Mice (C57B1/6, n = 26) underwent a 50% SBR or sham operation and were then given orogastric EGFR inhibitor (ZD1839, 50 mg/kg/day) or vehicle. After 3 days, indices of adaptation (wet weight, crypt depth, and villus height) and apoptotic index (number of apoptotic bodies per crypt) were calculated in the ileum. The expression of proliferating cell nuclear antigen (PCNA) and activated EGFR was measured by Western blotting. Results. ZD1839 prevented EGFR activation and the normal postresection increases in ileal wet weight, villus height, and crypt depth. Enterocyte proliferation was reduced twofold in the SBR group by ZD1839. Although not statistically significant, rates of enterocyte apoptosis were the highest in the inhibitor-treated mice. Conclusion. Following massive SBR, pharmacologic inhibition of the EGFR attenuates proliferation and the normal adaptive response of the intestine. These results more directly confirm the requirement of a functional EGFR as a mediator of the postresection adaptation response. This study demonstrates an in vivo application of a novel selective EGFR inhibitor and offers a unique experimental model to gain mechanistic insight into understanding postresection intestinal adaptation.