Jin Xu1,2, Zhengze Xue1,3, Cheng Zhang1,3, Yuan Liu1,4, Ronald W Busuttil1, Jiamin Zhang5, Jerzy W Kupiec-Weglinski1, Haofeng Ji1. 1. Division of Liver and Pancreas Transplantation, Department of Surgery, Dumont-UCLA Transplant Center, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA. 2. Department of Pancreatic Surgery, Shengjing Hospital, China Medical University, Shenyang, China. 3. Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. 4. Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. 5. Department of Surgery, People's Hospital of Jinhua, Jinhua, Zhejiang, China.
Abstract
BACKGROUND: Liver ischemia and reperfusion injury (IRI) is a major complication of liver transplant, hepatectomy, and hemorrhagic shock. The cyclin-dependent kinase 2 (CDK2) acts as a pivotal regulator of cell cycle and proliferation. METHODS: This study evaluated the modulation and therapeutic potential of CDK2 inhibition in a mouse model of partial liver warm IRI. RESULTS: Liver IR-triggered intrinsic CDK2 expression, peaking by 0.5 hour of reperfusion and maintaining a high-level throughout 1 to 24 hours. Roscovitine, a specific CDK2 inhibitor, prevented liver IR-mediated damage with abolished serum alanine aminotransferase levels and reserved liver pathology. CDK2 inhibition-mediated liver protection was accompanied by decreased macrophage/neutrophil infiltration, diminished hepatocyte apoptosis, abolished toll like receptor 4 signaling and downstream gene inductions (C-X-C motif ligand-10, Tumor necrosis factor-α, interleukin-1β, and interleukin-6), yet augmented interleukin-10 expression. In vitro, CDK2 inhibition by Roscovitine suppressed macrophage TLR4 activation and further depressed downstream inflammatory signaling (myeloid differentiation factor 88, interferon regulatory transcription factor 3, p38, c-Jun N-terminal kinase, and extracellular-regulated kinase). CONCLUSIONS: Our novel findings revealed the critical role of CDK2 in hepatic cytoprotection and homeostasis against liver IRI. As CDK2 inhibition regulated local immune response and prevented hepatocyte death, this study provided the evidence for new treatment approaches to combat IRI in liver transplant.
BACKGROUND:Liver ischemia and reperfusion injury (IRI) is a major complication of liver transplant, hepatectomy, and hemorrhagic shock. The cyclin-dependent kinase 2 (CDK2) acts as a pivotal regulator of cell cycle and proliferation. METHODS: This study evaluated the modulation and therapeutic potential of CDK2 inhibition in a mouse model of partial liver warm IRI. RESULTS: Liver IR-triggered intrinsic CDK2 expression, peaking by 0.5 hour of reperfusion and maintaining a high-level throughout 1 to 24 hours. Roscovitine, a specific CDK2 inhibitor, prevented liver IR-mediated damage with abolished serum alanine aminotransferase levels and reserved liver pathology. CDK2 inhibition-mediated liver protection was accompanied by decreased macrophage/neutrophil infiltration, diminished hepatocyte apoptosis, abolished toll like receptor 4 signaling and downstream gene inductions (C-X-C motif ligand-10, Tumor necrosis factor-α, interleukin-1β, and interleukin-6), yet augmented interleukin-10 expression. In vitro, CDK2 inhibition by Roscovitine suppressed macrophage TLR4 activation and further depressed downstream inflammatory signaling (myeloid differentiation factor 88, interferon regulatory transcription factor 3, p38, c-Jun N-terminal kinase, and extracellular-regulated kinase). CONCLUSIONS: Our novel findings revealed the critical role of CDK2 in hepatic cytoprotection and homeostasis against liver IRI. As CDK2 inhibition regulated local immune response and prevented hepatocyte death, this study provided the evidence for new treatment approaches to combat IRI in liver transplant.
Authors: Haofeng Ji; Xiuda Shen; Feng Gao; Bibo Ke; Maria Cecilia S Freitas; Yoichiro Uchida; Ronald W Busuttil; Yuan Zhai; Jerzy W Kupiec-Weglinski Journal: Hepatology Date: 2010-10 Impact factor: 17.425
Authors: David E MacCallum; Jean Melville; Sheelagh Frame; Kathryn Watt; Sian Anderson; Athos Gianella-Borradori; David P Lane; Simon R Green Journal: Cancer Res Date: 2005-06-15 Impact factor: 12.701
Authors: Haofeng Ji; Xiu-da Shen; Yu Zhang; Feng Gao; Cynthia Y Huang; William W Chang; Coney Lee; Bibo Ke; Ronald W Busuttil; Jerzy W Kupiec-Weglinski Journal: Liver Transpl Date: 2012-06 Impact factor: 5.799
Authors: K A Fitzgerald; E M Palsson-McDermott; A G Bowie; C A Jefferies; A S Mansell; G Brady; E Brint; A Dunne; P Gray; M T Harte; D McMurray; D E Smith; J E Sims; T A Bird; L A O'Neill Journal: Nature Date: 2001-09-06 Impact factor: 49.962
Authors: Christina Patrick; Leslie Crews; Paula Desplats; Wilmar Dumaop; Edward Rockenstein; Cristian L Achim; Ian P Everall; Eliezer Masliah Journal: Am J Pathol Date: 2011-04 Impact factor: 4.307
Authors: Yuan Liu; Tianfei Lu; Cheng Zhang; Zhengze Xue; Jin Xu; Ronald W Busuttil; Qiang Xia; Ning Xu; Jerzy W Kupiec-Weglinski; Haofeng Ji Journal: Transplantation Date: 2019-08 Impact factor: 4.939