Research Papers:

Repressor and activator protein accelerates hepatic ischemia reperfusion injury by promoting neutrophil inflammatory response

Chang Xian Li, Chung Mau Lo, Qizhou Lian, Kevin Tak-Pan Ng, Xiao Bing Liu, Yuen Yuen Ma, Xiang Qi, Oscar Wai Ho Yeung, Vinay Tergaonkar, Xin Xiang Yang, Hui Liu, Jiang Liu, Yan Shao and Kwan Man _

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Oncotarget. 2016; 7:27711-27723. https://doi.org/10.18632/oncotarget.8509

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Chang Xian Li1,3, Chung Mau Lo1,2,3, Qizhou Lian4, Kevin Tak-Pan Ng1,3, Xiao Bing Liu1,3, Yuen Yuen Ma1,3, Xiang Qi1,3, Oscar Wai Ho Yeung1,3, Vinay Tergaonkar 5, Xin Xiang Yang1, Hui Liu1,3, Jiang Liu1,3, Yan Shao1,3, Kwan Man1,2,3

1Department of Surgery, The University of Hong Kong, Hong Kong, China

2Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The University of Hong Kong, Hong Kong, China

3Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China

4Department of Medicine, The University of Hong Kong, Hong Kong, China

5Institute of Molecular and Cellular Biology, Biopolis, Singapore

Correspondence to:

Kwan Man, e-mail: [email protected]

Keywords: liver transplantation, hepatic ischemia reperfusion injury, neutrophils migration, inflammatory response, nuclear factor-κB

Received: February 22, 2016     Accepted: March 22, 2016     Published: March 30, 2016


Repressor and activator protein (Rap1) directly regulates nuclear factor-κB (NF-κB) dependent signaling, which contributes to hepatic IRI. We here intended to investigate the effect of Rap1 in hepatic ischemia reperfusion injury (IRI) and to explore the underlying mechanisms. The association of Rap1 expression with hepatic inflammatory response were investigated in both human and rat liver transplantation. The effect of Rap1 in hepatic IRI was studied in Rap1 knockout mice IRI model in vivo and primary cells in vitro. Our results showed that over expression of Rap1 was associated with severe liver graft inflammatory response, especially in living donor liver transplantation. The results were also validated in rat liver transplantation model. In mice hepatic IRI model, the knockout of Rap1 reduced hepatic damage and hepatic inflammatory response. In primary cells, the knockout of Rap1 suppressed neutrophils migration activity and adhesion in response to liver sinusoidal endothelial cells through down-regulating neutrophils F-Actin expression and CXCL2/CXCR2 pathway. In addition, the knockout of Rap1 also decreased production of pro-inflammatory cytokines/chemokines in primary neutrophils and neutrophils-induced hepatocyte damage. In conclusion, Rap1 may induce hepatic IRI through promoting neutrophils inflammatory response. Rap1 may be the potential therapeutic target of attenuating hepatic IRI.

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