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

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

Studies of the immunological activities of the outer membrane protein from escherichia coli.

The outer membrane protein (OMP) prepared from Escherichia coli was found to be a potent mitogen for murine B cells and to be capable of inducing polyclonal antibody formation as well as a proliferative response. Spleen cells from nude mice responded equally as well to OMP as those from their normal litter-mates, whereas nylon-wool-purified T cells or thymocytes failed to respond. The proliferative response was dependent on the presence of macrophages. The macrophage dependency of the polyclonal antibody response seemed to be less than that of the proliferation. OMP was mitogenic for lipopolysaccharide (LPS)-resistant C3H/HeJ spleen cells, further indicating that OMP is an unique B-cell mitogen distinct from LPS. OMP also enhanced the specific antibody response sixty-seven-fold to an optimal dose of sheep red blood cells (SRBC) in vitro. The kinetics of the response, however, was not altered from that of cultures without OMP. The anti-SRBC response of spleen cells from C3H/HeJ mice was also enhanced by the addition of OMP, suggesting that the adjuvant effects were not due to the LPS in the preparation. Antibody responses in vitro to TI-1 antigens, trinitrophenyl-LPS (Boivin) (TNP-LPS(B)) and TNP-Brucella abortus, were not enhanced in the presence of OMP. In contrast OMP enhanced the response to TI-2 antigens, TNP-LPS(W) (Westphal) and dinitrophenyl-Ficoll and T cells were shown to be required for these augmented antibody responses. Enhancement was not seen in nude mouse spleen cell cultures but was seen when nylon-wool-purified T cells were added to the cultures