Background Sepsis is a systemic inflammatory response syndrome caused by severe infections. LDK378, a second-generation ALK inhibitor, exhibits a potential anti-inflammatory function against sepsis. Micro- and macro-circulatory dysfunctions are pivotal elements of the pathogenesis of severe sepsis and septic shock. We hypothesized that LDK378 can improve micro- and macro-circulation of septic rats, therefore improving the outcome of survival via blocking the ALK-STING pathway to attenuate inflammatory injuries. Methods A septic rat model was established by the cecal ligation and puncture (CLP) method. A total of 60 rats were randomized into three groups: a sham group, CLP group, and CLP + LDK378 group (n = 20 in each group). Five rats were randomly selected from each group for the mechanism study; the remaining 15 rats in each group were involved in a survival curve examination. A sidestream dark field video microscope was used to record sublingual microcirculation and mean arterial pressure (MAP) and levels of inflammatory cytokine secretion were examined at 6 h, 30 h, and 54 h after CLP surgery. Expressions of TANK binding kinase 1 (TBK1) and its downstream targets were determined, and histological alterations to the heart, lungs, and kidneys were examined at 54 h after CLP surgery. Results We found the group that received LDK378 treatment showed increased MAP levels compared to the CLP group at 30 h and 54 h. Meanwhile, LDK378 ameliorated the perfused small vessel density and microvascular flow index, decreased the expression of TNF-a and IL-6, and upregulated the expression of IL-10 in comparison with the CLP group. LDK378 injections also downregulated the expression of TBK1 and its downstream targets. Furthermore, LDK378 treatment significantly reduced sepsis-induced organ injuries, therefore improving survival rates. Conclusions These findings demonstrate that LDK378 treatment can improve microcirculation and reduce organ injuries in CLP-induced septic rats via the regulation of inflammatory cytokine secretion and the downstream signaling components of the ALK-STING pathway.

中文翻译：

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LDK378 通过减轻盲肠结扎和穿刺诱导的脓毒症大鼠模型中的 STING 介导的炎症损伤来改善微循环和大循环。

背景脓毒症是由严重感染引起的全身炎症反应综合征。LDK378 是一种第二代 ALK 抑制剂，对脓毒症具有潜在的抗炎作用。微循环和大循环功能障碍是严重脓毒症和感染性休克发病机制的关键因素。我们假设 LDK378 可以改善脓毒症大鼠的微循环和大循环，因此通过阻断 ALK-STING 通路减轻炎症损伤来改善生存结果。方法采用盲肠结扎穿刺（CLP）法建立脓毒症大鼠模型。共 60 只大鼠随机分为三组：假手术组、CLP 组和 CLP + LDK378 组（每组 n = 20）。每组随机选取5只大鼠进行机制研究；每组其余15只大鼠进行生存曲线检查。侧流暗视野视频显微镜用于记录舌下微循环和平均动脉压（MAP），并在CLP手术后6小时、30小时和54小时检查炎性细胞因子分泌水平。确定了 TANK 结合激酶 1 (TBK1) 及其下游靶标的表达，并在 CLP 手术后 54 小时检查了心脏、肺和肾脏的组织学改变。结果我们发现，与 CLP 组相比，接受 LDK378 治疗的组在 30 小时和 54 小时时 MAP 水平升高。同时，与CLP组相比，LDK378改善了灌注的小血管密度和微血管流量指数，降低了TNF-α和IL-6的表达，上调了IL-10的表达。LDK378 注射还下调了 TBK1 及其下游靶标的表达。此外，LDK378 治疗显着减少了败血症引起的器官损伤，从而提高了存活率。结论 这些研究结果表明，LDK378 治疗可通过调节炎性细胞因子分泌和 ALK-STING 通路的下游信号成分来改善 CLP 诱导的脓毒症大鼠的微循环并减少器官损伤。