Epidermal growth factor receptor signaling regulates Bax and Bcl-w expression and apoptotic responses during intestinal adaptation in mice.
OBJECTIVE
Normal intestinal adaptation to massive small-bowel resection requires intact epidermal growth factor receptor signaling and consists of increased enterocyte proliferation and apoptosis. Although emphasis has been placed on understanding the regulation of proliferation, few studies have evaluated the mechanism and contribution of apoptosis to the adaptation response. We sought to test the hypothesis that epidermal growth factor receptor signaling regulates specific Bcl-2 family members (Bax and Bcl-w) to direct apoptosis and adaptation after massive small-bowel resection.


METHODS
Laser capture microdissection microscopy permitted measurement of Bax and Bcl-w messenger RNA expression in crypt and villus enterocytes in control conditions and under epidermal growth factor receptor-inhibited (waved-2 mice) or stimulated (epidermal growth factor transgenic mice) conditions after a 50% small-bowel resection or sham operation. Resection-induced adaptation was then studied in Bax-null and Bcl-w-null mice under control circumstances and after epidermal growth factor receptor stimulation.


RESULTS
When compared with Bcl-w, the most significant expression changes were observed with Bax and took place within crypt enterocytes. Epidermal growth factor receptor stimulation resulted in a decreased ratio of Bax to Bcl-w expression and decreased rates of apoptosis. Bax-null mice had no apoptosis response to small-bowel resection and displayed an amplified adaptation response to the administration of epidermal growth factor. Bcl-w-null mice had poor survival and impaired adaptation to small-bowel resection, an effect that was rescued by crossbreeding these mice with epidermal growth factor transgenic mice.


CONCLUSIONS
The crypt expression of Bax and Bcl-w is influenced by epidermal growth factor receptor signaling and is key for the regulation of apoptosis. Epidermal growth factor receptor stimulation, coupled with apoptosis inhibition, may provide a novel strategy to amplify adaptation responses in patients after massive intestinal loss.
Bernal
Nicole P
NP
Division of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
Stehr
Wolfgang
W
Coyle
Rebecca
R
Erwin
Christopher R
CR
Warner
Brad W
BW
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D066246:ErbB Receptors / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D051028:bcl-2-Associated X Protein / Q000172:deficiency / Q000235:genetics*
D051017:Apoptosis Regulatory Proteins; C101155:Bcl2l2 protein, mouse; D011506:Proteins; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; D066246:ErbB Receptors