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    • Therefore the current study was designed to

    2019-05-17

    Therefore, the current study was designed to investigate the effect of LS on coagulopathy and organ dysfunction in rats with endotoxemia induced by LPS, and to explore possible pathophysiological mechanisms. Previous studies have demonstrated that thromboelastography (TEG) appears to be a reliable monitor to detect the early endotoxin-related activation of coagulation and the consecutive consumption of coagulation factors and platelets. Therefore, we used TEG to measure the change of coagulation function induced by LPS in this study.
    Methods
    Results
    Discussion It had been reported that inflammation-related coagulopathy, such as microvascular thrombosis, participated in the pathogenesis of multiple organ dysfunction syndrome. The medical strategies aimed at mitigating systemic coagulopathy may improve organ injury in sepsis. Our study demonstrated that LS administration partially attenuated hemostasis derangement and mitigated multiple organ dysfunctions in the in vivo rat model of endotoxemia. The protective effects of LS in acute endotoxemic rats may be associated with the inhibition of plasma IL-6 production. Comparable to our previous study, the analysis of TEG parameters revealed that the shortened clotting time (R-time) and the increased kinetics of clot formation (K-time and α-angle) were found in the initial etizolam vendor of LPS infusion in this experiment. Thereafter, the rate of clot formation was diminished, and eventually followed by the attenuation in the strength of the blood clot (the MA value). This indicates the reduction in the number and function of platelets and fibrinogen, which was indeed confirmed in our study (shown in Figs. 4 and 5). These results are comparable to alterations in clinical status when severe sepsis patients usually developed coagulation dysfunction to hypocoagulable profiles (defined as the value of MA < 51 mm). In addition to calcium sensitizer and potassium channel opener, LS is a potent PDE-III inhibitor which increases intracellular cAMP levels and leads to platelet inhibition. Therefore, an in vitro study showed that LS decreased the blood aggregation response in a dose-dependent correlation. However, in our in vivo study, the LS application in a clinical relevant concentration did not significantly change coagulation and platelet function in rats (Fig. 3). This is consistent with in vivo studies either in human or in rats, showing that LS has no significant effect on blood coagulation in a normal condition. Intriguingly, in this study, the changes of TEG parameters and decreases of platelet count and plasma fibrinogen levels after acute LPS administration in rats were attenuated by LS, suggesting that the therapeutic effect of LS is most likely associated with alleviating the coagulation activation and minimizing the degree of consumptive coagulopathy. This is contrary to Bent and Plaschke\'s data, showing that LS had no significant effects on the function and numbers of platelets in endotoxemic rats. The difference between our study and theirs could be due to: (i) LPS dosage, 4 mg/kg vs. 8 mg/kg; (ii) initial infusion time of LS after LPS administration, co-treatment vs. 24 h post-treatment; (iii) duration of LS infusion, 4 h vs. 1 h; and (iv) analysis time after LPS infusion, 4 h vs. 1 and 6 days. However, our results demonstrated that LS alleviated the LPS-induced rise of biochemical parameters of the liver and the kidney and pathological deteriorations of the lung. Thus, LS may attenuate organ injury and dysfunction induced by endotoxemia, at least in part, through its anticoagulation effect. In addition to coagulation, inflammation plays an important role in the pathogenesis of sepsis. Several studies have showed that LS offers potential effects on inhibition of the inflammatory response in patients with decompensated heart failure. Furthermore, in rats with endotoxemia, LS can inhibit the production of IL-1β and IL-6, but not TNF-α. Indeed, our study showed that the increase in serum IL-6 levels was significantly attenuated after LS treatment in endotoxemic rats. Van der Poll et al. demonstrated that anti-IL-6 markedly attenuates endotoxin-induced activation of coagulation, monitored by the plasma levels of the prothrombin fragment F1+2 and thrombin-antithrombin III complexes in mild endotoxemia in chimpanzees. Thus, the protective effects of LS on coagulation in endotoxemic rats may be mediated partly by the inhibition of plasma IL-6 production.