Bax deficiency rescues resection-induced enterocyte apoptosis in mice with perturbed EGF receptor function.
BACKGROUND
Adaptation after massive smallbowel resection (SBR) is associated with increased cell turnover, increased rates of enterocyte proliferation, and apoptosis. Epidermal growth factor receptor (EGFR) inhibition attenuates adaptation and increases apoptosis. Intestinal levels of bax appear to correlate with EGFR signaling. This study tested the hypothesis that bax is required for the exaggerated postresection apoptosis induced by perturbed EGFR signaling.


METHODS
Waved-2 mice with impaired EGFR signaling were crossbred with bax-null mice. Offspring were subjected to either 50% proximal SBR or sham operation (bowel transection and reanastomosis). After 7 days, parameters of adaptation (villus height, wet weight), proliferation (% Ki-67 immunostaining of crypt cells), and apoptosis (# apoptotic bodies per crypt) were recorded in the remnant ileum.


RESULTS
Enterocyte apoptosis was increased in waved-2 mice and prevented in bax-null mice after SBR. The accelerated apoptosis in the waved-2 mice was rescued in the context of deficient bax expression. Other parameters of adaptation were restored in the bax-null/waved-2 mice.


CONCLUSIONS
Bax is required for the induction of postresection enterocyte apoptosis. Defective EGFR signaling augments resection-induced enterocyte apoptosis via a mechanism that also requires bax expression. These data implicate a link between EGFR signaling and bax in the genesis of postresection apoptosis and adaptation.
Division of Pediatric Surgery, Cincinnati Children's Hospital Medical Center, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3039, USA.
Marcus D
MD
Jarboe
Russell J
RJ
Juno
Nicole P
NP
Bernal
Andrew W
AW
Knott
Yufang
Y
Zhang
Christopher R
CR
Erwin
Brad W
BW
Warner
D000222:Adaptation, Physiological; D000818:Animals; D017209:Apoptosis; D020895:Enterocytes / Q000473:pathology*; D066246:ErbB Receptors / Q000502:physiology*; D007421:Intestine, Small / Q000601:surgery*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2; D015398:Signal Transduction; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D066246:ErbB Receptors