FK 409 Ameliorates Small-for-Size Liver Graft Injury by Attenuation of Portal Hypertension and Down-Regulation of Egr-1 Pathway

Objective:To investigate whether low-dose nitric oxide donor FK 409 could attenuate small-for-size graft injury in liver transplantation using small-for-size grafts. Summary Background Data:The major concern of live donor liver transplantation is small-for-size graft injury at the early phase after transplantation. Novel therapeutic strategies should be investigated. Methods:We employed a rat orthotopic liver transplantation model using small-for-size (40%) graft. FK 409 was given at 30 minutes before graft harvesting (2 mg/kg) to the donor and immediately after reperfusion (1 mg/kg) to the recipient (FK group). Graft survival, intragraft genes expression, portal hemodynamics, and hepatic ultrastructural changes were compared between the 2 groups. Results:Seven-day graft survival rates in the FK group were significantly improved compared with those of rats not receiving FK 409 (control group; 80% versus 28.6%, P = 0.018). In the FK group, portal pressure was significantly decreased within the first 60 minutes after reperfusion whereas in the control group, transient portal hypertension was observed. Intragraft expression (both mRNA and protein) of early growth response-1, endothelin-1, endothelin-1 receptor A, tumor necrosis factor-α, macrophage-inflammatory protein-2, and inducible nitric oxide synthase was significantly down-regulated accompanied with up-regulation of heme oxygenase-1, A20, interferon-γ-inducible protein-10, and interleukin-10 during the first 24 hours after reperfusion. Hepatic ultrastructure, especially the integrity of sinusoids was well protected in the FK group. Conclusions:Low-dose FK 409 rescues small-for-size grafts in liver transplantation by attenuation of portal hypertension and amelioration of acute phase inflammatory response by down-regulation of Egr-1, together with prior induction of heat shock proteins.

[1]  S. Fan,et al.  Intragraft gene expression profiles by cDNA microarray in small‐for‐size liver grafts , 2003, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[2]  S. Fan,et al.  Distinct intragraft response pattern in relation to graft size in liver transplantation , 2003, Transplantation.

[3]  S. Fan,et al.  Graft Injury in Relation to Graft Size in Right Lobe Live Donor Liver Transplantation: A Study of Hepatic Sinusoidal Injury in Correlation With Portal Hemodynamics and Intragraft Gene Expression , 2003, Annals of surgery.

[4]  M. Takaoka,et al.  Nitric oxide inhibits endothelin-1 production through the suppression of nuclear factor kappa B. , 2002, Clinical science.

[5]  A. Ting,et al.  A20 Inhibits Tumor Necrosis Factor (TNF) Alpha-Induced Apoptosis by Disrupting Recruitment of TRADD and RIP to the TNF Receptor 1 Complex in Jurkat T Cells , 2002, Molecular and Cellular Biology.

[6]  D. Geller,et al.  Blockade of the L‐arginine/NO synthase pathway worsens hepatic apoptosis and liver transplant preservation injury , 2002, Hepatology.

[7]  N. Kalia,et al.  FK409 inhibits both local and remote organ damage after intestinal ischaemia , 2002, The Journal of pathology.

[8]  F. Gao,et al.  Ischemia-Reperfusion : The Roles of PI 3-Kinase , Akt , and Endothelial Nitric Oxide Nitric Oxide Mediates the Antiapoptotic Effect of Insulin in Myocardial , 2002 .

[9]  C. Ferran,et al.  A20 protects mice from D‐galactosamine/lipopolysaccharide acute toxic lethal hepatitis , 2002, Hepatology.

[10]  Frank Scholle,et al.  Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. , 2002, Gastroenterology.

[11]  R. Strieter,et al.  IFN-γ-Inducible Protein-10 (CXCL10) Is Hepatoprotective During Acute Liver Injury Through the Induction of CXCR2 on Hepatocytes1 , 2001, The Journal of Immunology.

[12]  T. Collins,et al.  Extinguishing Egr‐1‐dependent inflammatory and thrombotic cascades following lung transplantation , 2001 .

[13]  M. Yoneda,et al.  Macrophage inflammatory protein-2 induced by TNF-α plays a pivotal role in concanavalin A-induced liver injury in mice , 2001 .

[14]  S. Schwartz.  A protective player in the vascular response to injury , 2001, Nature Medicine.

[15]  K. Man,et al.  Liver transplantation in rats using small-for-size grafts: a study of hemodynamic and morphological changes. , 2001, Archives of surgery.

[16]  G. Tiegs,et al.  Inducible nitric oxide synthase is critical for immune-mediated liver injury in mice. , 2001, The Journal of clinical investigation.

[17]  Nigel Mackman,et al.  Egr-1, a master switch coordinating upregulation of divergent gene families underlying ischemic stress , 2000, Nature Medicine.

[18]  T. Sueda,et al.  Cardioprotective effects of FK409, a nitric oxide donor, after isolated rat heart preservation for 16 hours. , 2000, The Annals of thoracic surgery.

[19]  A. Kakita,et al.  Prior induction of heat shock proteins by a nitric oxide donor attenuates cardiac ischemia/reperfusion injury in the rat. , 2000, Transplantation.

[20]  J Zaky,et al.  Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury. , 1999, The Journal of clinical investigation.

[21]  H. Mashimo,et al.  Lessons from genetically engineered animal models. IV. Nitric oxide synthase gene knockout mice. , 1999, The American journal of physiology.

[22]  H. Hsieh,et al.  Nitric oxide regulates shear stress-induced early growth response-1. Expression via the extracellular signal-regulated kinase pathway in endothelial cells. , 1999, Circulation research.

[23]  P. Kamath,et al.  Endothelin‐1 modulates intrahepatic resistance in a rat model of noncirrhotic portal hypertension , 1999, Hepatology.

[24]  A. Lentsch,et al.  Interleukin‐10 suppresses hepatic ischemia/reperfusion injury in mice: Implications of a central role for nuclear factor κB , 1999, Hepatology.

[25]  D. Dhar,et al.  Beneficial effects of FK409, a novel nitric oxide donor, on reperfusion injury of rat liver. , 1998, Transplantation.

[26]  R. Bentley,et al.  Apoptosis of sinusoidal endothelial cells is a critical mechanism of preservation injury in rat liver transplantation , 1998, Hepatology.

[27]  M. Mayer,et al.  Hsp70 chaperone systems: diversity of cellular functions and mechanism of action. , 1998, Biological chemistry.

[28]  Hong-Gang Wang,et al.  Endothelin-1 selectively contracts portal vein through both ETA and ETB receptors in isolated rabbit liver. , 1997, American journal of physiology. Gastrointestinal and liver physiology.

[29]  M. Clemens,et al.  Endothelin-1 induces direct constriction of hepatic sinusoids. , 1994, The American journal of physiology.

[30]  H. Fusamoto,et al.  Endothelin‐1 is involved in the pathogenesis of ischemia/reperfusion liver injury by hepatic microcirculatory disturbances , 1994, Hepatology.

[31]  P. Fung,et al.  Plasma nitric oxide is associated with the occurrence of moderate to severe acute graft-versus-host disease in haemopoietic stem cell transplant recipients. , 2001, Haematologica.

[32]  M. Yoneda,et al.  Macrophage inflammatory protein-2 induced by TNF-alpha plays a pivotal role in concanavalin A-induced liver injury in mice. , 2001, Journal of hepatology.