Abstract 330: LDK378 Attenuates Macro and Microcirculation in a Sepsis Rat Model Induced by Cecal Ligation and Puncture

Abstract

Background: Sepsis is a systemic inflammatory response syndrome caused by severe infections. Myocardial dysfunction has been associated with increased mortality in septic patients. Previous studies have demonstrated that LDK378, a second-generation ALK inhibitor, is a potential anti-inflammatory mediator. We investigated the effects of LDK378 on macro and microcirculation in a rat model of cecal ligation and puncture (CLP) induced sepsis. Hypothesis: LDK378 attenuates the deleterious effects of sepsis on macro- and micro- circulation in CLP induced septic rats. Method: Fifteen male rats weighing between 450-550g were randomized into three groups: Sham, CLP, and CLP+LDK378. Our rat sepsis model was induced by 50% cecum ligation and two punctures with a 20-gauge needle. LDK378 (20mg/kg) was administered intraperitoneal (IP) to animals at 0h, 24h and 48 hours after CLP operation in the CLP+LDK378 group. Cardiac output (CO), mean arterial pressure (MAP); sublingual microcirculation including perfused small vessel density (PVD) and microcirculatory flow index (MFI) were measured at 6h, 30h and 54h after CLP. Results: Significant reduction in CO, MAP, MFI and PVD were observed in both CLP and CLP+LDK378 groups at 6h, 30h and 54h. However, the levels of CO, MAP, MFI and PVD reduction were significantly better in the CLP+LDK378 group when compared with the CLP group at 30h and 54h after CLP. Conclusion: LDK378 attenuates macro and microcirculation parameters in our rat model of sepsis.