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Sunitinib alleviates hepatic ischemia reperfusion injury by inhibiting the JAK2/STAT pathway and promoting the M2 polarization of macrophages

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机构: [1]Wuhan Univ, Wuhan Hosp 3, Tongren Hosp, Dept Anesthesiol, Wuhan, Peoples R China [2]Cent South Univ, Xiangya Hosp 3, Res Associate Dept Pathol, Changsha, Peoples R China [3]Cent South Univ, Xiangya Hosp 2, Dept Ultrasound Diag, Changsha, Peoples R China [4]Cent South Univ, Xiangya Hosp 2, Dept Pediat, Changsha, Peoples R China [5]Hengdong Cty Peoples Hosp, Dept Gen Surg, Hengyang, Hengdong County, Peoples R China [6]Cent South Univ, Xiangya Hosp 2, Dept Gen Surg, 139 Renmin Middle Rd, Changsha 410011, Peoples R China
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关键词: Sunitinib hepatic IRI JAK2 STAT macrophage polarization

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BackgroundHepatic ischemia reperfusion injury (IRI) is a common liver surgery complication. This study aims to explore the effect and potential mechanism of Sunitinib - a multi-target tyrosine kinase inhibitor - on hepatic IRI.MethodsWe established a hepatic IRI model using C57BL/6 mice, and integrated 40 mg/kg of Sunitinib, solely or combined with 100 mu g/kg of coumermycin A1 (C-A1), in the treatment strategy. H&E staining, TUNEL assay, and detection of serum ALT and AST activities were used to assess liver damage. Further, ELISA kits and Western Blots were utilized to determine IL-1 beta, TNF-alpha, IL-6, CXCL10, and CXCL2 levels. Primary macrophages, once isolated, were cultured in vitro with either 2 nM of Sunitinib, or Sunitinib in conjunction with 1 mu M of C-A1, to gauge their influence on macrophage polarization. qPCR and Western blot were conducted to examine the level of p-STAT1/STAT1, p-STAT3/STAT3, p-JAK2/JAK2, and M1/M2 polarization markers. To quantify immune cell infiltration, we applied Immunofluorescence.ResultsSunitinib pretreatment significantly alleviated liver injury and reduced p-STAT1/STAT1, p-STAT3/STAT3, p-JAK2/JAK2 levels. In vitro, Sunitinib treatment curbed M1 polarization induced by LPS + IFN-gamma and bolstered M2 polarization triggered by IL-4. C-A1 application upregulated JAK2/STAT pathway phosphorylation and promoted LPS + IFN-gamma-induced M1 polarization, which was reversed by Sunitinib treatment. In IL-4-stimulated macrophages, application of C-A1 activated the JAK2/STAT pathway and decreased M2-type macrophages, which was reversed by Sunitinib treatment either.ConclusionSunitinib is capable of guiding the polarization of macrophages toward an M2-type phenotype via the inhibition of the JAK2/STAT pathway, thereby exerting a protective effect on hepatic IRI.

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出版当年[2023]版:
大类 | 4 区 医学
小类 | 3 区 毒理学 4 区 免疫学 4 区 药学
最新[2023]版:
大类 | 4 区 医学
小类 | 3 区 毒理学 4 区 免疫学 4 区 药学
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出版当年[2022]版:
Q2 PHARMACOLOGY & PHARMACY Q2 TOXICOLOGY Q3 IMMUNOLOGY
最新[2023]版:
Q2 PHARMACOLOGY & PHARMACY Q2 TOXICOLOGY Q3 IMMUNOLOGY

影响因子: 最新[2023版] 最新五年平均 出版当年[2022版] 出版当年五年平均 出版前一年[2021版] 出版后一年[2023版]

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第一作者机构: [1]Wuhan Univ, Wuhan Hosp 3, Tongren Hosp, Dept Anesthesiol, Wuhan, Peoples R China
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通讯机构: [6]Cent South Univ, Xiangya Hosp 2, Dept Gen Surg, 139 Renmin Middle Rd, Changsha 410011, Peoples R China [*1]Department of General Surgery, The Second Xiangya Hospital, Central South University, No. 139 Renmin Middle Road, Furong District, Changsha, 410011, China
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