Multiple selectin blockade with a small molecule inhibitor downregulates liver chemokine expression and neutrophil infiltration after hemorrhagic shock

Background: The purpose of this study was to investigate the regulatory eff ect of a small molecule selectin inhibitor in the liver by examining the fu nctional, structural, and survival response of animals subjected to hemorrh agic shock and to determine the liver infiltration of neutrophils and the r egulation of chemokine expression, Selectins play an important role in the development of the lesions associated with ischemia/reperfusion and hemorrh agic shock. Blocking individually the selectin family of adhesion molecules with monoclonal antibodies has resulted in better organ function and survi val. To our knowledge, there are no studies demonstrating the beneficial ef fect of multiple selectin blockade with a small molecule inhibitor under co nditions of hemorrhagic shock. Methods: Forty-eight Sprague-Dawley rats were subjected to hemorrhagic shoc k. Three groups of animals were included (n = 16/group), i.e., the sham, co ntrol, and treated groups, which received a small molecule selectin inhibit or (TBC-1269) at 25 mg/kg body weight after the bleeding began, The followi ng parameters were evaluated: fluid requirements during resuscitation, live r injury tests (aspartate aminotransferase, alanine aminotransferase), live r histology and myeloperoxidase, and macrophage inflammatory protein-2 mRNA and cytokine-induced neutrophil chemoattractant mRNA in liver tissue, and animal survival at 3 days. Statistical analysis included Student's t test a nd analysis of variance when indicated. Results: Significant improvement in liver function and histology was noted in the treated group, Survival was also improved, although it is not known whether liver failure was the most proximate cause of lethality. Infiltrati on of neutrophils, measured by tissue myeloperoxidase, was significantly de creased in livers of treated animals. No significant changes were noted in fluid requirements. The small molecule selectin inhibitor group showed a do wn-regulating effect on liver macrophage inflammatory protein-2 and cytokin e-induced neutrophil chemoattractant mRNA expression associated with less a ccumulation of neutrophils in the liver. Conclusion: This study supports the role that selectins play in the pathoge nesis of hemorrhagic shock. The mechanism of protection seen after multiple selectin blockade (TBC-1269) centered, in part, around the infiltration of liver neutrophils, probably dependent on the induction of macrophage infla mmatory protein-2 and cytokine-induced neutrophil chemoattractant mRNA expr ession in liver tissue.