Sunitinib alleviates hepatic ischemia reperfusion injury by inhibiting the JAK2/STAT pathway and promoting the M2 polarization of macrophages.
Immunopharmacol Immunotoxicol
; 46(5): 672-684, 2024 Oct.
Article
em En
| MEDLINE
| ID: mdl-39155607
ABSTRACT
BACKGROUND:
Hepatic 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.METHODS:
We established a hepatic IRI model using C57BL/6 mice, and integrated 40 mg/kg of Sunitinib, solely or combined with 100 µg/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-1ß, TNF-α, 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 µM 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.RESULTS:
Sunitinib 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-γ and bolstered M2 polarization triggered by IL-4. C-A1 application upregulated JAK2/STAT pathway phosphorylation and promoted LPS + IFN-γ-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.CONCLUSION:
Sunitinib 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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Traumatismo por Reperfusão
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Transdução de Sinais
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Janus Quinase 2
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Sunitinibe
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Macrófagos
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Camundongos Endogâmicos C57BL
Limite:
Animals
Idioma:
En
Revista:
Immunopharmacol Immunotoxicol
/
Immunopharmacol. immunotoxicol
/
Immunopharmacology and immunotoxicology
Assunto da revista:
ALERGIA E IMUNOLOGIA
/
FARMACOLOGIA
/
TOXICOLOGIA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China