title: p38 MAPK regulates Bax activity and apoptosis in enterocytes at baseline and after intestinal resection.
abstract: Increased apoptosis in crypt enterocytes is a key feature of intestinal adaptation following massive small bowel resection (SBR). Expression of the proapoptotic factor Bax has been shown to be required for resection-induced apoptosis. It has also been demonstrated that p38-α MAPK (p38) is necessary for Bax activation and apoptosis in vitro. The present studies were designed to test the hypothesis that p38 is a key regulator of Bax activation during adaptation after SBR in vivo. Enterocyte expression of p38 was deleted by tamoxifen administration to activate villin-Cre in adult mice with a floxed Mapk14 (p38-α) gene. Proximal 50% SBR or sham operations were performed on wild-type (WT) and p38 intestinal knockout (p38-IKO) mice under isoflurane anesthesia. Mice were killed 3 or 7 days after operation, and adaptation was analyzed by measuring intestinal morphology, proliferation, and apoptosis. Bax activity was quantified by immunoprecipitation, followed by Western blotting. After SBR, p38-IKO mice had deeper crypts, longer villi, and accelerated proliferation compared with WT controls. Rates of crypt apoptosis were significantly lower in p38-IKO mice, both at baseline and after SBR. Levels of activated Bax were twofold higher in WT mice after SBR relative to sham. In contrast, activated Bax levels were reduced by 67% in mice after p38 MAPK deletion. Deleted p38 expression within the intestinal epithelium leads to enhanced adaptation and reduced levels of enterocyte apoptosis after massive intestinal resection. p38-regulated Bax activation appears to be an important mechanism underlying resection-induced apoptosis.
authors.affiliation: Department of Surgery, Division of Pediatric Surgery, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Wakeman
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.forename: Jethrina A
authors.initials: JA
authors.lastname: Santos
authors.forename: Wambui S
authors.initials: WS
authors.lastname: Wandu
authors.forename: John E
authors.initials: JE
authors.lastname: Schneider
authors.forename: Mark E
authors.initials: ME
authors.lastname: McMellen
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Leinicke
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Erwin
authors.forename: Brad W
authors.initials: BW
authors.lastname: Warner
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D020895:Enterocytes / Q000166:cytology* / Q000502:physiology*; D007422:Intestines / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery; D051379:Mice; D018345:Mice, Knockout; D012778:Short Bowel Syndrome / Q000473:pathology / Q000503:physiopathology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C494827:Bax protein, mouse; D051028:bcl-2-Associated X Protein; D048051:p38 Mitogen-Activated Protein Kinases