Heme oxygenase-1 protects rat liver against warm ischemia/reperfusion injury via TLR2/TLR4-triggered signaling pathways

AIM:To investigate the efficacy and molecularmechanisms of induced heme oxygenase(HO)-1 in protecting liver from warm ischemia/reperfusion(I/R)injury.METHODS:Partial warm ischemia was produced in the left and middle hepatic lobes of SD rats for 75min,followed by 6 h of reperfusion.Rats were treated...

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Published in:World journal of gastroenterology : WJG 2015-03, Vol.21 (10), p.2937-2948
Main Authors: Huang, Han-Fei, Zeng, Zhong, Wang, Kun-Hua, Zhang, Hai-Yan, Wang, Shuai, Zhou, Wen-Xiang, Wang, Zhan-Bo, Xu, Wang-Gang, Duan, Jian
Format: Article
Language:English
Subjects:
Adaptor Proteins, Vesicular Transport - metabolism
Animals
Basic Study
Cytoprotection
Disease Models, Animal
Enzyme Inhibitors - pharmacology
Heme
Heme Oxygenase (Decyclizing) - antagonists & inhibitors
Heme Oxygenase (Decyclizing) - metabolism
injury
Toll
Liver - drug effects
Liver - enzymology
Liver - immunology
Liver - pathology
Male
Myeloid Differentiation Factor 88 - metabolism
oxygenase-1
Ischemia
Protoporphyrins - pharmacology
Rats, Sprague-Dawley
reperfusion
Reperfusion Injury - enzymology
Reperfusion Injury - etiology
Reperfusion Injury - immunology
Reperfusion Injury - pathology
Reperfusion Injury - prevention & control
Signal Transduction - drug effects
Toll-Like Receptor 2 - drug effects
Toll-Like Receptor 2 - metabolism
Toll-Like Receptor 4 - drug effects
Toll-Like Receptor 4 - metabolism
Warm Ischemia - adverse effects
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Summary:AIM:To investigate the efficacy and molecularmechanisms of induced heme oxygenase(HO)-1 in protecting liver from warm ischemia/reperfusion(I/R)injury.METHODS:Partial warm ischemia was produced in the left and middle hepatic lobes of SD rats for 75min,followed by 6 h of reperfusion.Rats were treated with saline,cobalt protoporphyrin(Co PP)or zinc protoporphyrin(Zn PP)at 24 h prior to the ischemia insult.Blood and samples of ischemic lobes subjected to ischemia were collected at 6 h after reperfusion.Serum transaminases level,plasma lactate dehydrogenase and myeloperoxidase activity in liver were measured.Liver histological injury and inflammatory cell infiltration were evaluated by tissue section and liver immunohistochemical analysis.We used quantitative reverse transcription polymerase chain reaction to analyze liver expression of inflammatory cytokines and chemokines.The cell lysates were subjected to immunoprecipitation with anti-Toll-IL-1R-containing adaptor inducing interferon-β(TRIF)and anti-myeloid differentiation factor 88(My D88),and then the immunoprecipitates were analyzed by SDS-PAGE and immunoblotted with the indicated antibodies.RESULTS:HO-1 protected livers from I/R injury,as evidenced by diminished liver enzymes and wellpreserved tissue architecture.In comparison with Zn PP livers 6 h after surgery,Co PP treatment livers showed a significant increase inflammatory cell infiltration of lymphocytes,plasma cells,neutrophils and macrophages.The Toll-like receptor(TLR)-4 and TANK binding kinase1 protein levels of rats treated with Co PP significantly reduced in TRIF-immunoprecipitated complex,as compared with Zn PP treatment.In addition,pretreatment with Co PP reduced the expression levels of TLR2,TLR4,IL-1R-associated kinase(IRAK)-1 and tumor necrosis factor receptor-associated factor 6 in My D88-immunoprecipitated complex.The inflammatory cytokines and chemokines m RNA expression rapidly decreased inCo PP-pretreated liver,compared with the Zn PP-treated group.However,the expression of negative regulators Tollinteracting protein,suppressor of cytokine signaling-1,IRAK-M and Src homology 2 domain-containing inositol-5-phosphatase-1 in Co PP treatment rats were markedly up-regulated as compared with Zn PP-treated rats.CONCLUSION:HO-1 protects liver against I/R injury by inhibiting TLR2/TLR4-triggered My D88-and TRIFdependent signaling pathways and increasing expression of negative regulators of TLR signaling in rats.
ISSN:1007-9327
2219-2840
DOI:10.3748/wjg.v21.i10.2937