Tumor necrosis factor-alpha inhibition reduces CXCL-8 levels but fails to prevent fibrin generation and does not improve outcome in a rabbit model of endotoxic shock
Keywords: 
Antibodies, Monoclonal/pharmacology
Fibrin/metabolism
Interleukin-8/metabolism
Shock, Septic/metabolism
Tumor Necrosis Factor-alpha/antagonists & inhibitors
Issue Date: 
2003
Publisher: 
Elsevier
ISSN: 
1532-6543
Citation: 
Rodriguez-Wilhelmi P, Montes R, Matsukawa A, Nariuchi H, Hurtado V, Montes M, et al. Tumor necrosis factor-alpha inhibition reduces CXCL-8 levels but fails to prevent fibrin generation and does not improve outcome in a rabbit model of endotoxic shock. J Lab Clin Med 2003 Apr;141(4):257-264.
Abstract
The effects of a monoclonal antibody (mAb) to tumor necrosis factor-alpha (TNF-alpha) were examined in a rabbit model of endotoxic shock. Intravenous administration of lipopolysaccharide (100 microg/kg/hr) for 6 hours (n = 11) increased TNF-alpha levels. Fibrinogen was partially consumed, and fibrin deposits were seen in kidney and lungs at 24 hours. Mortality at 24 hours was 64%. Levels of interleukin-8 (aka CXCL-8) were notably increased. Mean arterial pressure (MAP) and leukocyte counts decreased, whereas creatinine levels were enhanced. The anti-TNF-alpha mAb (20 mg/kg i.v. bolus + 5 mg/kg/h i.v. for the first 90 minutes) (n = 10) efficiently inhibited the TNF-activity. Rabbits exhibited lower CXCL-8 levels; MAP improved, the decrease in leukocyte counts was partially prevented and creatinine levels were lower, but fibrinogen, fibrin deposits in kidneys and lungs and mortality, 55%, were similar to the LPS group. Rabbits that did not survive exhibited lower fibrinogen levels, more fibrin in kidneys and lungs and higher CXCL-8 and creatinine levels than survivors, while there were no differences in TNF-alpha, MAP and leukocytes. Thus, the inhibition of TNF-alpha, although beneficial through lowering CXCL-8 levels, is not enough to improve the outcome, which could be partly due to the inability to prevent the fibrin deposits formation in kidneys and lungs.

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