Upregulation of lung chemokines associated with hemorrhage is reversed with a small molecule multiple selectin inhibitor

Background: Hemorrhage can modify the leukocyte-endothelial cell response l eading to tissue injury. The selectin family of adhesion molecules and chem okines mediate the leukocyte-endothelial cell interaction, resulting in neu trophil sequestration and activation. This work studies whether a small mol ecule inhibitor of selectins can ameliorate the effect of hemorrhage on che mokine expression and neutrophil infiltration in the lung. We also aimed to assess the regulatory effect of this small molecule inhibitor of selectins in the lung functional and structural response of animals subjected to hem orrhagic shock. Study Design: We subjected 36 Sprague-Dawley rats to uncontrolled hemorrhag ic shock for a period of 150 minutes. Three groups of animals were included (n = 12 per group)-the sham, control, and treated groups, with the latter receiving a small molecule selectin inhibitor (TBC-1269) at 25 mg/kg, which was given after tail artery transection. The following measurements were e valuated: fluid requirements during resuscitation for 150 minutes; PO2/FIO2 ratio, lung water, and lung histology, lung myeloperoxidase and lung macro phage inflammatory protein-2 (MIP-2) mRNA and cytokine induced neutrophil c hemoattractant mRNA at 6 hours. Statistical analysis included Student's t-t est and ANOVA. Results: There was significant improvement in lung function as expressed by PO2/FIO2 ratio and wet to dry lung water ratio in the treated group. There were no significant changes in fluid requirements between the three groups . Neutrophil infiltration, measured by tissue myeloperoxidase, was signific antly (p < 0.05) decreased in the lungs of the treated animals. Lung histol ogy was considerably improved in the treated group. The small molecule sele ctin inhibitor had a profound downregulating effect on macrophage inflammat ory protein-2 and cytokine-induced neutrophil chemoattractant as expressed in lung tissue. Conclusions: Our study confirms the key role that selectins play in the pat hogenesis of hemorrhagic shock. The multiple selectin blockade allowed for better function and structure of the lung. The mechanism of protection may be secondary to the downregulation of chemokine expression and neutrophil i nfiltration. (J Am Coll Surg 1999;189:546-553. (C) 1999 by the American Col lege of Surgeons).