title: Bcl-2 inhibits gut epithelial apoptosis induced by acute lung injury in mice but has no effect on survival.
abstract: Gut epithelial apoptosis is increased in human studies and animal models of noninfectious inflammation and sepsis. Elevated intestinal cell death appears to be physiologically significant in sepsis. Previous studies demonstrate that overexpression of the antiapoptotic protein Bcl-2 in the gut epithelium of transgenic mice is associated with improved survival from Pseudomonas aeruginosa pneumonia and cecal ligation and puncture. The functional significance of elevated gut apoptosis in noninfectious inflammation has not been examined. We hypothesized that intestinal apoptosis would be detrimental to survival in noninfectious critical illness. To address this issue, acute lung injury (ALI) was induced with intratracheal injection of lipopolysaccharide (LPS, 800 microg) in wild-type (WT) FVB/N mice and transgenic mice that overexpress Bcl-2 in their intestinal epithelium. Guts were harvested at 12, 24, 48, and 72 h and assessed for apoptosis by both hematoxylin and eosin and active caspase-3 staining in 100 contiguous crypts. ALI increased gut epithelial apoptosis 12 h after LPS instillation compared with shams (P < 0.01), whereas overexpression of Bcl-2 decreased intestinal apoptosis compared with WT animals with ALI when assayed by active caspase-3 (P < 0.05). Plasma levels of tumor necrosis factor alpha, interleukin (IL)-6, and IL-10 were similar between WT and transgenic animals with ALI, both of which had elevated IL-10 levels at 12 h and elevated IL-6 levels at 24 h compared with sham animals. In a separate experiment, transgenic and WT animals with ALI were followed for mortality to determine whether gut overexpression of Bcl-2 conferred a survival advantage. Survival at 10 days was 73% in WT animals (n = 33) and 65% in Bcl-2 animals (n = 23, P = ns). These results indicate that while gut epithelial apoptosis is elevated in multiple models of critical illness, prevention of intestinal cell death by overexpression of Bcl-2 is associated with a disparate survival effect between sepsis and noninfectious inflammation.
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Kareem D
authors.initials: KD
authors.lastname: Husain
authors.forename: Paul E
authors.initials: PE
authors.lastname: Stromberg
authors.forename: Pardis
authors.initials: P
authors.lastname: Javadi
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Buchman
authors.forename: Irene E
authors.initials: IE
authors.lastname: Karl
authors.forename: Richard S
authors.initials: RS
authors.lastname: Hotchkiss
authors.forename: Craig M
authors.initials: CM
authors.lastname: Coopersmith
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000032:analysis; D019446:Endotoxemia / Q000139:chemically induced / Q000401:mortality; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000097:blood / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D007413:Intestinal Mucosa / Q000033:anatomy & histology / Q000737:chemistry / Q000502:physiology*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology*; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000401:mortality / Q000503:physiopathology*; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000187:drug effects / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; C482199:lipopolysaccharide, E coli O55-B5; D016753:Interleukin-10; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases