Selective inhibition of the epidermal growth factor receptor impairs intestinal adaptation after small bowel resection.
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.


CONCLUSIONS
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.
O'Brien
David P
DP
Division of Pediatric Surgery, Cincinnati Children's Hospital Medical Center, Ohio 45229, USA.
Nelson
Lindsey A
LA
Williams
Jodi L
JL
Kemp
Christopher J
CJ
Erwin
Christopher R
CR
Warner
Brad W
BW
D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020895:Enterocytes / Q000166:cytology / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000502:physiology*; D000077156:Gefitinib; D007421:Intestine, Small / Q000166:cytology / Q000502:physiology* / Q000601:surgery*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011799:Quinazolines / Q000494:pharmacology; D012778:Short Bowel Syndrome / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology
D004791:Enzyme Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib