P-selectin and chemokine response after liver ischemia and reperfusion.
BACKGROUND
P-selectin plays a major role in the earliest phase of polymorphonuclear neutrophil recruitment in the hepatic microvasculature after liver ischemia and reperfusion. Leukocyte cytokine chemoattractants (chemokines) cause polymorphonuclear neutrophil activation in ischemia and reperfusion injury. In this study, we examined the role of P-selectin in the production of chemokines in the liver and lung inflammatory response after 90 minutes of warm ischemia.


METHODS
Thirty-six C57BL/6 mice were subjected to partial liver ischemia for 90 minutes. Three groups of animals were included (n = 12 per group): the sham group, the ischemic control group, and the P-selectin-deficient gene targeted mice group. After 3 hours, we evaluated liver injury measurements, serum chemokines (MIP[macrophage inflammatory protein]-1alpha and MIP-2), liver and lung tissue myeloperoxidase, and liver and lung histology. Statistical analysis included ANOVA, Student-Newman-Keuls', and Kruskal-Wallis Multiple Comparison Z-value tests.


RESULTS
P-selectin-deficient mice showed significant decreases in liver enzyme levels (p < 0.05) and marked decreases in serum MIP-1alpha and MIP-2 chemokine determinations (p < 0.05) when compared with ischemic controls. Neutrophil infiltration was significantly ameliorated in the liver (p < 0.05) and markedly decreased in the lung, as reflected by decreased MPO levels. Improved histopathologic features in the liver and lung were observed in the P-selectin-deficient mice group compared with ischemic controls.


CONCLUSIONS
Our study confirms the key role of P-selectin in the pathogenesis of liver ischemia and reperfusion and the production of chemokines. P-selectin-deficient animals had improved liver function, decreased neutrophil infiltration, and decreased MIP- 1alpha and MIP-2 responses.
Martinez-Mier
G
G
Borgess Research Institute, Department of Surgery Research Sciences, Kalamazoo, MI 49001, USA.
Toledo-Pereyra
L H
LH
McDuffie
J E
JE
Warner
R L
RL
Ward
P A
PA
D000704:Analysis of Variance; D000818:Animals; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines / Q000097:blood*; D046508:Culture Techniques; D004195:Disease Models, Animal; D007511:Ischemia / Q000097:blood* / Q000473:pathology / Q000601:surgery*; D008099:Liver / Q000098:blood supply* / Q000378:metabolism*; D008111:Liver Function Tests; D019402:Macrophage Inflammatory Proteins / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019007:P-Selectin / Q000097:blood*; D011336:Probability; D012016:Reference Values; D015427:Reperfusion Injury / Q000097:blood*
D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines; D019402:Macrophage Inflammatory Proteins; D019007:P-Selectin