Sepsis has been identified as the most common cause of acute kidney injury (AKI) in intensive care units. Lipopolysaccharide (LPS) induces the production of several proinflammatory cytokines including tumor necrosis factor (TNF)-alpha, a major pathogenetic factor in septic AKI. c-Fos/activator protein (AP)-1 controls the expression of these cytokines by binding directly to AP-1 motifs in the cytokine promoter regions. T-5224 is a new drug developed by computer-aided drug design that selectively inhibits c-Fos/AP-1 binding to DNA. In this study, we tested whether T-5224 has a potential inhibitory effect against LPS-induced AKI, by suppressing the TNF-alpha inflammatory response and other downstream effectors.
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To test this hypothesis, male C57BL/6 mice at 7 weeks old were divided into three groups (control, LPS and T-5224 groups). Mice in the control group received saline intraperitoneally and polyvinylpyrrolidone solution orally. Mice in the LPS group were injected intraperitoneally with a 6 mg/kg dose of LPS and were given polyvinylpyrrolidone solution immediately after LPS injection. In the T-5224 group, mice were administered T-5224 orally at a dose of 300 mg/kg immediately after LPS injection. Serum concentrations of TNF-alpha, interleukin (IL)-1beta, IL-6 and IL-10 were measured by ELISA. Moreover, the expression of intercellular adhesion molecule (ICAM)-1 mRNA in kidney was examined by quantitative real-time RT-PCR. Finally, we evaluated renal histological changes.
Fibrinolysis is the process of degradation of a fibrin clot into so-called fibrin degradation products (FDPs) of which the d-dimers are best known. Following coagulation, tissue-type plasminogen activator (tPA) induces fibrinolysis by activation of plasminogen into plasmin which enzymatically degrades fibrin into FDPs. To avoid excess clot lysis activity, the fibrinolytic system is under tight control of alpha 2-antiplasmin, plasminogen activator inhibitor-1 (PAI-1), and thrombin activated fibrinolysis inhibitor (TAFI). However, a disbalance in pro- and antifibrinolytic factors can result in either hyper- or hypofibrinolysis, which may contribute to the risk for bleeding or thrombosis, respectively. In trauma and cirrhosis the increased bleeding tendency is attributed to a hyperfibrinolytic state in combination with a rebalanced hemostatic system [1, 2]. In pregnancy, a hypercoaguable state may occur in conjunction with reduced fibrinolysis [3]. In sepsis, the initial procoagulant state is associated with attenuated fibrinolysis due to elevated PAI-1, which may advance towards an uncontrolled syndrome of disseminated intravascular coagulation (DIC), with a clinical bleeding tendency [4, 5]. Factor XIII (FXIII) activated by thrombin crosslinks fibrin strands in order to strengthen the fibrin clot. Low FXIII activity levels are seen in sepsis and could contribute to an enhanced bleeding diathesis in severe septic shock [6].
In patients with cirrhosis, the fibrinolytic pathway is activated by an increased endothelial release of tissue plasminogen activator (t-PA), decreased hepatic clearance of t-PA, decreased thrombin activatable fibrinolysis inhibitor, and decreased synthesis of alpha-2 antiplasmin and plasminogen activator inhibitor.1,3 Hyperfibrinolysis in cirrhotic patients usually causes mucocutaneous bleeding, but it can also cause gastrointestinal bleeding.4
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