Multiple selectin blockade with a small-molecule selectin inhibitor does not affect survival after a second inflammatory challenge with nonlethal LPS.
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.
Borgess Research Institute, Trauma, Surgery Research Sciences, and Molecular Biology, Kalamazoo, Michigan 49048, USA.
Roberto
R
Anaya-Prado
J Ricardo
JR
Ramos-Kelly
Luis H
LH
Toledo-Pereyra
Jon
J
Walsh
Peter A
PA
Ward
D000818:Animals; D001794:Blood Pressure; D002339:Carotid Arteries / Q000601:surgery; D004195:Disease Models, Animal; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology*; D007601:Jugular Veins / Q000601:surgery; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008297:Male; D009336:Necrosis; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation; D019087:Selectins / Q000502:physiology*; D012771:Shock, Hemorrhagic / Q000401:mortality / Q000503:physiopathology*; D016019:Survival Analysis; D013997:Time Factors
D008070:Lipopolysaccharides; D019087:Selectins; D009195:Peroxidase