Pre-conditioning with tanshinone IIA attenuates the ischemia/reperfusion injury caused by liver grafts via regulation of HMGB1 in rat Kupffer cells.
OBJECTIVE
We have evaluated the protective mechanism of tanshinone IIA in ischemia/reperfusion injury (IRI) induced by liver grafts, revealing novel supplementary immunotherapy for liver transplantation.


METHODS
The tanshinone IIA preconditioning group (TP group) was pretreated with tanshinone IIA via intraperitoneal injection for 1 week before receiving orthotopic liver transplantation with hepatic arterial ischemia for 30min. The sham-operation group (SO group), control graft group (CG group) and IRI group were pretreated with an equivalent volume of normal saline. The IRI group and CG group received orthotopic liver transplantation with or without hepatic arterial ischemia. Rats were sacrificed at each time point, serum was collected for ELISA detection, and Kupffer cells (KCs) were isolated to extract total protein and RNA for western blotting and real-time PCR, respectively.


RESULTS
The levels of TNF-α and IL-4 in the TP group were significantly lower than those of in the IRI group; meanwhile the IL-10 and TGF-β levels were significantly higher than in the IRI group. The protein and mRNA expression levels of HMGB1 were significantly lower in TP group than in the IRI group at each time point. The TLR-4, Myd88, NLRP3 and p-NF-κb p65 expression levels in the TP groups were significantly lower than those in the IRI group, while the PTEN, PI3K and AKT phosphorylation levels in the TP groups were significantly higher than those in the IRI group.


CONCLUSIONS
Tanshinone IIA attenuates IRI caused by liver grafts via down-regulation of the HMGB1-TLR-4/NF-κb pathway in KCs and activation of PTEN/PI3K/AKT pathway, suggesting a potential role for prevention of liver cell IRI during liver transplantation.
Department of Hepatobiliary Surgery and Chongqing Key Laboratory of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, PR China.
Xuanfei
X
Li
Department of Hepatobiliary Surgery, Suining Central Hospital, Suining, Sichuan, 629000, PR China.
Yakun
Y
Wu
Department of Hepatobiliary Surgery and Chongqing Key Laboratory of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, PR China.
Wenfeng
W
Zhang
Department of Hepatobiliary Surgery and Chongqing Key Laboratory of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, PR China. Electronic address: gongjianping11@126.com.
Jianping
J
Gong
Department of Hepatobiliary Surgery and Chongqing Key Laboratory of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, PR China. Electronic address: chenyaocqmu@sina.com.
Yao
Y
Cheng
D045784:Abietanes / Q000494:pharmacology*; D000818:Animals; D024243:HMGB1 Protein / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008107:Liver Diseases / Q000188:drug therapy / Q000378:metabolism; D016031:Liver Transplantation / Q000379:methods; D008297:Male; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D045784:Abietanes; D024243:HMGB1 Protein; D016753:Interleukin-10; D015847:Interleukin-4; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D019869:Phosphatidylinositol 3-Kinases; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C104200:Hbp1 protein, rat; C021751:tanshinone
HMGB1; Ischemia reperfusion injury; Kupffer cells; Liver transplantation; Tanshinone IIA