Inhibition of intestinal epithelial apoptosis and survival in a murine model of pneumonia-induced sepsis.
BACKGROUND
Increased intestinal epithelial apoptosis is present in both human autopsy studies and animal models of sepsis. Whether altering gut apoptosis decreases mortality in sepsis induced by pathogenic bacteria outside the gut is unknown.


OBJECTIVE
To determine if decreasing levels of intestinal cell death improves survival in a murine model of Pseudomonas aeruginosa pneumonia-induced sepsis.


METHODS
Prospective study in which transgenic mice that overexpress the antiapoptotic protein Bcl-2 in their intestinal epithelium (n = 25) and control littermates (n = 26) were subjected to intratracheal injection of P aeruginosa.


METHODS
Survival at 7 postoperative days, compared between the 2 groups. Secondary outcomes included quantification of gut epithelial apoptosis.


RESULTS
Survival in transgenic mice that overexpress Bcl-2 in the intestinal epithelium was 40% (10/25) compared with 4% (1/26) in control littermates 7 days after intratracheal injection of P aeruginosa (P =.001), with differences in survival noted within 24 hours of surgery. Overexpression of Bcl-2 was associated with a decrease in gut epithelial apoptosis demonstrated by active caspase 3 staining, the terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling assay, and hematoxylin-eosin staining.


CONCLUSIONS
In this murine model, inhibiting gut epithelial apoptosis by overexpression of Bcl-2 was associated with a survival advantage in P aeruginosa pneumonia-induced sepsis. These results suggest that intestinal epithelial apoptosis may play a role in sepsis-related mortality.
Coopersmith
Craig M
CM
Department of Surgery, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8109, St Louis, MO 63110, USA. coopersmithc@msnotes.wustl.edu
Stromberg
Paul E
PE
Dunne
W Michael
WM
Davis
Christopher G
CG
Amiot
Daniel M
DM
Buchman
Timothy G
TG
Karl
Irene E
IE
Hotchkiss
Richard S
RS
D000818:Animals; D017209:Apoptosis; D018988:Bacterial Translocation; D053148:Caspase 3; D020169:Caspases; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D019254:Genes, bcl-2; D020287:In Situ Nick-End Labeling; D007413:Intestinal Mucosa / Q000382:microbiology / Q000473:pathology / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D018410:Pneumonia, Bacterial; D011446:Prospective Studies; D011552:Pseudomonas Infections / Q000503:physiopathology*; D018805:Sepsis / Q000503:physiopathology*; D016019:Survival Analysis
D016207:Cytokines; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases