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 leading to tissue injury. The selectin family of adhesion molecules and chemokines mediate the leukocyte-endothelial cell interaction, resulting in neutrophil sequestration and activation. This work studies whether a small molecule inhibitor of selectins can ameliorate the effect of hemorrhage on chemokine 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 hemorrhagic shock.


METHODS
We subjected 36 Sprague-Dawley rats to uncontrolled hemorrhagic 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 evaluated: fluid requirements during resuscitation for 150 minutes; PO2/FIO2 ratio, lung water, and lung histology, lung myeloperoxidase and lung macrophage inflammatory protein-2 (MIP-2) mRNA and cytokine induced neutrophil chemoattractant mRNA at 6 hours. Statistical analysis included Student's t-test 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 significantly (p < 0.05) decreased in the lungs of the treated animals. Lung histology was considerably improved in the treated group. The small molecule selectin inhibitor had a profound downregulating effect on macrophage inflammatory protein-2 and cytokine-induced neutrophil chemoattractant as expressed in lung tissue.


CONCLUSIONS
Our study confirms the key role that selectins play in the pathogenesis 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 infiltration.
Ramos-Kelly
J R
JR
Borgess Research Institute, Surgery Research Sciences and Molecular Biology, Kalamazoo, MI 49001, USA.
Toledo-Pereyra
L H
LH
Jordan
J A
JA
Rivera-Chavez
F A
FA
Dixon
R A
RA
Ward
P A
PA
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D015536:Down-Regulation; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008358:Mannose / Q000031:analogs & derivatives; D008362:Mannosides / Q000494:pharmacology; D009504:Neutrophils / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019087:Selectins / Q000502:physiology*; D012771:Shock, Hemorrhagic / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation
D001713:Biphenyl Compounds; D008362:Mannosides; D019087:Selectins; C108700:bimosiamose disodium; D009195:Peroxidase; D008358:Mannose