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

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...

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Autores principales: Ge, Weiwei, Hu, Qiaohua, Fang, Xiangshao, Liu, Juanhua, Xu, Jing, Hu, Juntao, Liu, Xuefen, Ling, Qin, Wang, Yue, Li, He, Gao, Ming, Jiang, Longyuan, Yang, Zhengfei, Tang, Wanchun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378711/
https://www.ncbi.nlm.nih.gov/pubmed/30820191
http://dx.doi.org/10.1186/s12950-019-0208-0
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author Ge, Weiwei
Hu, Qiaohua
Fang, Xiangshao
Liu, Juanhua
Xu, Jing
Hu, Juntao
Liu, Xuefen
Ling, Qin
Wang, Yue
Li, He
Gao, Ming
Jiang, Longyuan
Yang, Zhengfei
Tang, Wanchun
author_facet Ge, Weiwei
Hu, Qiaohua
Fang, Xiangshao
Liu, Juanhua
Xu, Jing
Hu, Juntao
Liu, Xuefen
Ling, Qin
Wang, Yue
Li, He
Gao, Ming
Jiang, Longyuan
Yang, Zhengfei
Tang, Wanchun
author_sort Ge, Weiwei
collection PubMed
description 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.
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spelling pubmed-63787112019-02-28 LDK378 improves micro- and macro-circulation via alleviating STING-mediated inflammatory injury in a Sepsis rat model induced by Cecal ligation and puncture Ge, Weiwei Hu, Qiaohua Fang, Xiangshao Liu, Juanhua Xu, Jing Hu, Juntao Liu, Xuefen Ling, Qin Wang, Yue Li, He Gao, Ming Jiang, Longyuan Yang, Zhengfei Tang, Wanchun J Inflamm (Lond) Research 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. BioMed Central 2019-02-18 /pmc/articles/PMC6378711/ /pubmed/30820191 http://dx.doi.org/10.1186/s12950-019-0208-0 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Ge, Weiwei
Hu, Qiaohua
Fang, Xiangshao
Liu, Juanhua
Xu, Jing
Hu, Juntao
Liu, Xuefen
Ling, Qin
Wang, Yue
Li, He
Gao, Ming
Jiang, Longyuan
Yang, Zhengfei
Tang, Wanchun
LDK378 improves micro- and macro-circulation via alleviating STING-mediated inflammatory injury in a Sepsis rat model induced by Cecal ligation and puncture
title LDK378 improves micro- and macro-circulation via alleviating STING-mediated inflammatory injury in a Sepsis rat model induced by Cecal ligation and puncture
title_full LDK378 improves micro- and macro-circulation via alleviating STING-mediated inflammatory injury in a Sepsis rat model induced by Cecal ligation and puncture
title_fullStr LDK378 improves micro- and macro-circulation via alleviating STING-mediated inflammatory injury in a Sepsis rat model induced by Cecal ligation and puncture
title_full_unstemmed LDK378 improves micro- and macro-circulation via alleviating STING-mediated inflammatory injury in a Sepsis rat model induced by Cecal ligation and puncture
title_short LDK378 improves micro- and macro-circulation via alleviating STING-mediated inflammatory injury in a Sepsis rat model induced by Cecal ligation and puncture
title_sort ldk378 improves micro- and macro-circulation via alleviating sting-mediated inflammatory injury in a sepsis rat model induced by cecal ligation and puncture
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378711/
https://www.ncbi.nlm.nih.gov/pubmed/30820191
http://dx.doi.org/10.1186/s12950-019-0208-0
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