LDK378 improves micro- and macro-circulation via alleviating STING-mediated inflammatory injury in a Sepsis rat model induced by Cecal ligation and puncture

• Main Authors: Weiwei Ge, Qiaohua Hu, Xiangshao Fang, Juanhua Liu, Jing Xu, Juntao Hu, Xuefen Liu, Qin Ling, Yue Wang, He Li, Ming Gao, Longyuan Jiang, Zhengfei Yang, Wanchun Tang
• Format: Article
• Language: English
• Published: BMC 2019-02-01
• Series: Journal of Inflammation
• Subjects: LDK378; Sepsis; ALK-STING pathway; Inflammation
• Online Access: http://link.springer.com/article/10.1186/s12950-019-0208-0

Abstract 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.