The Protective Effects Of Clopidogrel, A Platelet Antagonist, On Sepsis In Rats

Objective:Sepsis is often associated with coagulation abnormalities. Platelets play an important role both in inflammatory and coagulation processes. Previous studies showed that in a rat model of endotoxemia, clopidogrel could attenuate the histological changes of liver and lung tissue, and reduce the production of cytokines (IL-6and TNF-a) and the expression of the high mobility group box1(HMGB1) in liver and lung tissues. In this study, SD rats were recruited to produce an animal model of sepsis and farther explore the impact of clopidogrel on the activation of platelets, leukocytes and endothelial cells, the interaction of platelets with leukocytes, the expression of tissue factor on leukocytes and survival percentage of rats during the sepsis.Method:A rat model of sepsis was established by cecal ligation and puncture (CLP). SD rats were randomly divided into4groups:(1) sham-operated group (Sham);(2)sham-operated group with clopidogrel sulfate treatment (Sham+CS);(3) CLP group (CLP);(4) CLP group with clopidogrel sulfate treatment (CLP+CS). The survival percentages were observed in each group within7days after operation. The flow cytometric analyses were employed to detect the activation of platelets and leukocytes, platelet-leukocyte coaggregates and tissue factor (TF) expression on leukocytes, and Elisa kits to detect the plasm content of ICAM-1, E-Selectin and PSGL-1.Results:(1) Compared with the Sham group, the mortality of the CLP group was markedly increased (p<0.05), and CS significantly reduced the mortality (p<0.05).(2) At24h after operation, compared with the Sham group, the expression of CD61on platelets and Mac-1on leukocytes, the percentage of platelet-leukocyte coaggregates and expression of tissue factor on leukocytes in CLP group were significantly enhanced; and all these values were significantly reduced in CLP+CS group (all p＜0.05).(3) At12h after operation, compared with Sham group, the plasma content of ICAM-1, E-Selectin of CLP group were significantly increased (p<0.05), and CS markedly decreased the upregulation of ICAM-1and E-Selectin (p<0.05). However, there was no significant effect of CS on the PSGL-1(p>0.05).At24h after operation, CS markedly decreased the upregulation of ICAM-1and PSGL-1(p<0.05). However, no significant effect of CS was found in the E-Selectin (p>0.05).Conclusion:1.During sepsis, CS could inhibit the activation of platelets, leukocytes and endothelial cells, the interaction of platelets with leukocytes and the expression of tissue factor on leukocytes;2.During sepsis, CS could improve the mortality of rats.