Risk and recovery of outflow obstrcution in living-related liver transplantation: The influence of liver perfusion on regeneration and outcome
Final Report Abstract
Focal hepatic venous outflow obstruction occurs frequently when MHV is transected, as done in extended hepatectomy and living liver donation. We demonstrated in a woodchuck model, that the median liver lobe of rodents such as the woodchuck, but also the rat, is suitable to study hepatic outflow obstruction. Using a rat model, we first observed that focal hepatic venous outflow obstruction could cause confluent parenchymal necrosis. Parenchymal recovery started via hepatocyte proliferation from the border zone. Drainage of the outflow obstructed territory was reestablished via formation of vascularized sinusoidal canals (VSC). Second, we hypothesized that reduction of hepatic arterial perfusion is aggravating the initial injury and is slowing down the process of spontaneous recovery. Therefore we performed experiments to investigate the role of arterial perfusion in respect to the recovery from focal outflow obstruction. According to the hepatic arterial buffer response theory, portal hypertension after partial hepatectomy causes a reduction of hepatic arterial perfusion. Hepatic arterial flow was either blocked by ligating the hepatic artery or reduced by performing a partial hepatectomy. We demonstrated, that reduced or lack of hepatic arterial perfusion aggravated the primary damage, decelerated the recovery process, and influenced the formation of vascular sinusoidal canals. Additional transplantation injury further aggravated the extent of damage and slowed down the recovery process under both experimental conditions compared to the “ligation only” situation. Third, we assessed a pharmacological strategy to reduce portal hypertension respectively enhance hepatic arterial perfusion by using L-Name and molsidomine to reduce or increase the portal pressure by either inhibition of nitric oxide production or substitution of nitric oxide. Reduction of hepatic arterial inflow via inhibition of nitric oxide production worsened the recovery from focal hepatic venous outflow obstruction. Drugs increasing hepatic arterial inflow need to be evaluated to reverse the hyperperfusion-induced impairment of the spontaneous course after focal hepatic venous outflow obstruction. Assessment of liver regeneration as needed in this project was improved by the constant development and refinement of image analysis algorithms as well as the establishment of an improved protocol for qPCR. Additional results generated in the first funding period were analyzed and published in the second funding period.
Publications
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Median liver lobe of woodchuck as a model to study hepatic outflow obstruction: a pilot study. Liver Int 2008, 28: 1236-1244
Dahmen U, Radtke A, Schroeder T, Chi H, Madrahimov N, Lu M, Schenk A, Peitgen HO, Dirsch O
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Small-for-size syndrome in the rat: does size or technique matter? J Surg Res 2008, 149: 15-26
Dahmen U, Madrahimov N, Madrahimova F, Ji Y, Schenk A, Dirsch O
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Quantitative evaluation and selection of reference genes in a rat model of extended liver resection. J Biomol Tech 2009, 20: 109-115
Xing W, Deng M, Zhang J, Huang H, Dirsch O, Dahmen U
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Statistical and economical efficiency in assessment of liver regeneration using defined sample size and selection in combination with a fully automated image analysis system. J Histochem Cytochem 2009, 57: 1075-1085
Deng M, Kleinert R, Huang H, He Q, Madrahimova F, Dirsch O, Dahmen U
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A fast and robust hepatocyte quantification algorithm including vein processing. BMC Bioinformatics 2010, 11: 124
Ivanovska T, Schenk A, Homeyer A, Deng M, Dahmen U, Dirsch O, Hahn HK, Linsen L
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Effect and risk of AEE788, a dual tyrosine kinase inhibitor, on regeneration in a rat liver resection model. Eur Surg Res 2011, 44: 82-95
Deng M, Huang H, Dirsch O, Dahmen U
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Hepatic arterial perfusion is essential for the spontaneous recovery from focal hepatic venous outflow obstruction in rats. Am J Transplant 2011, 11: 2342-2352
Huang H, Deng M, Jin H, Liu A, Dirsch O, Dahmen U
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Prolonged cold ischemia does not trigger lethal rejection or accelerate the acute rejection in two allogeneic rat liver transplantation models. J Surg Res 2011
Jin H, Dahmen U, Liu A, Huang H, Gu Y, Dirsch O
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The anti-proliferative side effects of AEE788, a tyrosine kinase inhibitor blocking both EGF- and VEGF-receptor, are liver-size-dependent after partial hepatectomy in rats. Invest New Drugs 2011, 29: 593-606
Deng M, Huang H, Jin H, Dirsch O, Dahmen U
