Attenuation of acute phase shear stress by somatostatin improves small‐for‐size liver graft survival

The major concern of living donor liver transplantation is small‐for‐size graft injury at the early phase after transplantation. Novel therapeutic strategies should be developed. To investigate the protective effect of somatostatin related to hemodynamic stress on small‐for‐size liver graft injury, we applied a treatment regimen of low‐dose somatostatin in a rat orthotopic liver transplantation model using small‐for‐size grafts (median, 38.7%; range, 35–42%). Somatostatin was given at 5 minutes before total hepatectomy and immediately after reperfusion in the recipient (20 μg/kg). Graft survival, portal hemodynamics, intragraft gene expression and hepatic ultrastructural changes were compared between the rats with or without somatostatin treatment. Seven‐day graft survival rates in the somatostatin treatment group were significantly improved compared to the control group (66.7% vs. 16.7%, P = 0.036). In the treatment group, portal pressure and hepatic surface blood flow were significantly decreased within the first 30 minutes after reperfusion, whereas in the control group, transient portal hypertension and excessive hepatic blood flow were observed. Intragraft expression (both messenger RNA and protein) of endothelin‐1 was significantly downregulated accompanied with upregulation of heme oxygenase‐1 and A20. Better preservation of liver function was found in the treatment group. Hepatic ultrastructure, especially the integrity of sinusoids, was well protected in the treatment group. In conclusion, low‐dose somatostatin rescues small‐for‐size grafts from acute phase injury in liver transplantation by attenuation of acute‐phase shear stress that resulted from transient portal hypertension. Liver Transpl 12:621–627, 2006. © 2006 AASLD.

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

[2]  J. V. Ferrer,et al.  Prevention by somatostatine and N-acetylcisteine of multiorgan failure mediated by oxidative stress after intestinal ischemia. , 1999, Transplantation Proceedings.

[3]  E. Kouroumalis,et al.  Bolus somatostatin but not octreotide reduces hepatic sinusoidal pressure by a NO‐independent mechanism in chronic liver disease , 2001, Alimentary pharmacology & therapeutics.

[4]  J. Sowers,et al.  17 beta-Estradiol attenuates voltage-dependent Ca2+ currents in A7r5 vascular smooth muscle cell line. , 1994, The American journal of physiology.

[5]  D. Pessayre,et al.  Potent induction of apoptosis in human hepatoma cell lines by targeted cytotoxic somatostatin analogue AN-238. , 2005, Journal of hepatology.

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

[7]  E. Furth,et al.  Somatostatin attenuates ischemic intestinal injury. , 1993, American journal of surgery.

[8]  伊藤 隆司.  Changes in portal venous pressure in the early phase after living-donor liver transplantation : pathogenesis and clinical implications , 2004 .

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

[10]  S. Fan,et al.  FK 409 Ameliorates Small-for-Size Liver Graft Injury by Attenuation of Portal Hypertension and Down-Regulation of Egr-1 Pathway , 2004, Annals of surgery.

[11]  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.

[12]  H. Volk,et al.  Heme oxygenase-1 gene transfer inhibits inducible nitric oxide synthase expression and protects genetically fat Zucker rat livers from ischemia-reperfusion injury. , 2002, Transplantation.

[13]  K. Hirohashi,et al.  Changes in portal venous pressure in the early phase after living donor liver transplantation: pathogenesis and clinical implications1,2 , 2003, Transplantation.

[14]  Peter Smeets,et al.  Modulation of Portal Graft Inflow: A Necessity in Adult Living-Donor Liver Transplantation? , 2003, Annals of surgery.

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

[16]  S. Fan,et al.  Portal hyperperfusion injury as the cause of primary nonfunction in a small‐for‐size liver graft‐successful treatment with splenic artery ligation , 2003, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[17]  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.

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

[19]  H. Miyauchi,et al.  End‐to‐side portocaval shunting for a small‐for‐size graft in living donor liver transplantation , 2004, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[20]  H. Qin,et al.  Somatostatin suppresses endothelin-1-induced rat hepatic stellate cell contraction via somatostatin receptor subtype 1. , 2001, Gastroenterology.

[21]  R. Casamitjana,et al.  Effects of somatostatin on splanchnic hemodynamics and plasma glucagon in portal hypertensive rats. , 1988, The American journal of physiology.

[22]  J. Bosch,et al.  Effects of bolus injections and continuous infusions of somatostatin and placebo in patients with cirrhosis: A double‐blind hemodynamic investigation , 1995, Hepatology.

[23]  S. Fan,et al.  Attenuation of Small‐for‐Size Liver Graft Injury by FTY720: Significance of Cell‐survival Akt Signaling Pathway , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[24]  J. Jeekel,et al.  Somatostatin Receptor Gene Therapy Combined With Targeted Therapy With Radiolabeled Octreotide: A New Treatment for Liver Metastases , 2002, Annals of surgery.

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

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