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.
基金:
Natural Science Foundation of Hunan Province China [2024JJ5493]
第一作者机构:[1]Wuhan Univ, Wuhan Hosp 3, Tongren Hosp, Dept Anesthesiol, Wuhan, Peoples R China
通讯作者:
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
推荐引用方式(GB/T 7714):
Li Mingxia,Tan Juan,Zhang Rongsen,et al.Sunitinib alleviates hepatic ischemia reperfusion injury by inhibiting the JAK2/STAT pathway and promoting the M2 polarization of macrophages[J].IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY.2024,46(5):672-684.doi:10.1080/08923973.2024.2390455.
APA:
Li, Mingxia,Tan, Juan,Zhang, Rongsen,Gong, Xiaoxiang,Xie, Jun...&Li, Xiaojing.(2024).Sunitinib alleviates hepatic ischemia reperfusion injury by inhibiting the JAK2/STAT pathway and promoting the M2 polarization of macrophages.IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY,46,(5)
MLA:
Li, Mingxia,et al."Sunitinib alleviates hepatic ischemia reperfusion injury by inhibiting the JAK2/STAT pathway and promoting the M2 polarization of macrophages".IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY 46..5(2024):672-684