The effects of anti-adhesion molecule
antibodies on the blockade of leukocyte-endothelial interactions have the potential of decreasing survival through possibly increased
infection vulnerability. The aim of this study was to determine the effect of a small-molecule
selectin inhibitor (TBC-1269) on both liver response and survival to a nonlethal
lipopolysaccharide (LPS) challenge after
hemorrhagic shock. Ninety-six Sprague-Dawley rats were subjected to a model of uncontrolled
hemorrhagic shock. Six groups of animals were included in this study (n = 16 per group):
sham/saline,
sham/LPS,
shock/saline,
shock/LPS,
shock/TBC1269, and
shock/
TBC-1269/LPS. Experimental design consisted of the development of hemorrhagick
shock (3 mL/100 g) in a 15-min period, tail
amputation and
drug administration at 30 min, and subsequent
resuscitation to maintain mean arterial pressure at 70mm Hg. A septic challenge was produced with 0.1 mg/kg of LPS (Escherichia coli type 78H4086; Sigma Chemical, St. Louis, MO) given intravenously via penile vein at 20 h. Liver injury tests (
alanine aminotransferase, ALT), liver
myeloperoxidase, liver histology, and 21-day survival were evaluated. Statistical analysis included the Bartlett test for equality of variance, a two-way analysis of variance (ANOVA), and overall followed by pairwise log-rank test for survival. Significant improvements in liver function and histology were observed in animals treated with
TBC-1269 with or without a nonlethal septic challenge. Neutrophil infiltration, as evidenced by liver
myeloperoxidase (MPO) was significantly decreased in animals treated with
TBC-1269 alone and those having LPS administration after
TBC-1269 treatment. We conclude that
TBC-1269, multisectin blocker, was effective in reducing liver damage even with the addition of a second inflammatory insult as the nonlethal LPS challenge used in this study.