Laparotomy prevents lethal endotoxemia in a murine sequential insult model by an IL-10-dependent mechanism.
Multiple organ dysfunction and death are common sequelae after mesenteric ischemia-reperfusion injury as seen with mesenteric revascularization and thoracoabdominal aortic aneurysm repair. A second insult such as bacterial pneumonia occurring subsequent to the ischemia-reperfusion injury may contribute to these untoward effects. We hypothesized the sequential visceral/lower torso ischemia-reperfusion and endotoxemia in a murine model would increase the magnitude of the proinflammatory cytokine response and decrease survival. C57BL/6 mice underwent 20 min of supraceliac occlusion (IR), sham laparotomy (LAP), or no initial insult (CTRL) followed by intraperitoneal injection of a lethal dose of endotoxin (LPS [lipopolysaccharide 50 mg/kg] or saline vehicle at 24 h. Serum cytokine levels were measured by enzyme-linked immunosorbent assay (IL-10, IL-6) or WEHI bioassay [tumor necrosis factor (TNF)], and survival was determined at 5 days. The role of IL-10 on the TNF response and survival was examined in a subset of mice given mouse anti IL-10 IgM (25 mg/kg intraperitoneally) 2 h prior to the initial insult. Survival after LPS was significantly different (P < 0.05) among the treatment groups (IR, 64%; LAP, 55%; CTRL, 11%) and appeared to trend directly with the magnitude of the initial operation. The serum IL-10 levels in the IR and LAP groups were significantly increased 4 h after the initial insult and remained elevated at 24 h. Peak serum TNF levels after LPS were significantly lower in the IR and LAP groups. Administration of anti IL-10 IgM resulted in uniform mortality and a significant increase in the peak TNF levels after LPS administration for all initial treatment groups. Endogenous production of IL-10 following laparotomy down-regulates the TNF response and improves survival after endotoxemia.
Back
M R
MR
Department of Surgery, University of Florida College of Medicine, Gainesville 32610-0286, USA.
Sarac
T P
TP
Moldawer
L L
LL
Welborn
M B
MB
Seeger
J M
JM
Huber
T S
TS
D000818:Animals; D001013:Aorta, Thoracic; D001018:Aortic Diseases / Q000150:complications; D003250:Constriction; D019446:Endotoxemia / Q000150:complications / Q000517:prevention & control*; D005260:Female; D007075:Immunoglobulin M / Q000627:therapeutic use; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000097:blood / Q000276:immunology / Q000502:physiology*; D007511:Ischemia / Q000150:complications*; D007813:Laparotomy; D008643:Mesentery / Q000098:blood supply; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009102:Multiple Organ Failure / Q000209:etiology* / Q000517:prevention & control; D011897:Random Allocation; D015427:Reperfusion Injury / Q000150:complications*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014781:Viscera / Q000098:blood supply*
D007075:Immunoglobulin M; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10