Limited therapeutic efficacy of thrombopoietin on the regeneration of steatotic livers.

Liver regeneration after partial hepatectomy is impaired in steatotic livers of leptin-deficient ob/ob mice. Previous studies have shown that thrombopoietin (TPO) promotes liver regeneration and improves liver cirrhosis by an increase of platelet counts and the expansion of hepatic progenitor cells. Herein we studied whether TPO exerts pro-proliferative and hepatoprotective effects and thereby improves the regenerative capacity of steatotic livers.

Hepatoprotection in bile duct ligated mice mediated by darbepoetin-α is not caused by changes in hepatobiliary transporter expression.

Aims: Darbepoetin-α (DPO), a long-acting erythropoietin analog, has been shown to protect the liver against cholestatic injury, to exert an antifibrotic effect, and to increase the survival time in a model of common bile duct ligation. Here we evaluate whether these tissue-protective effects are caused by DPO induced regulation of hepatobiliary transporters.

Main Methods: C57BL/6J mice underwent common bile duct ligation and were treated with either DPO or physiological saline.

A critical appraisal of the hemodynamic signal driving liver regeneration.

Background: Many aspects of the signaling mechanisms involved in the initiation of hepatic regeneration are under current investigation. Nevertheless, the actual mechanisms switching liver regeneration on and off are still unknown. Hemodynamic changes in the liver following partial hepatectomy have been suggested to be a primary stimulus in triggering liver regeneration.

Impact of portal branch ligation on tissue regeneration, microcirculatory response and microarchitecture in portal blood-deprived and undeprived liver tissue.

Partial ligation of portal branches leads to atrophy of the deprived lobes and hypertrophy of the intact lobes. In this study we investigated the microcirculatory response and their consequences on tissue regeneration after left-sided portal branch ligation (PBL) in Sprague-Dawley rats. At day 1 and 3 after PBL the hepatic microcirculation was assessed by intravital microscopy (IVM).

Regulation of hepatic blood flow: the hepatic arterial buffer response revisited.

The interest in the liver dates back to ancient times when it was considered to be the seat of life processes. The liver is indeed essential to life, not only due to its complex functions in biosynthesis, metabolism and clearance, but also its dramatic role as the blood volume reservoir. Among parenchymal organs, blood flow to the liver is unique due to the dual supply from the portal vein and the hepatic artery.

Mutation of mitochondrial ATP8 gene improves hepatic energy status in a murine model of acute endotoxemic liver failure.

Aims: Mitochondria not only generate and modulate bioenergy but also serve as biosensors for oxidative stress, and eventually become effector organelles for cell viability. Therefore, the implications of mitochondrial (dys)function in the development of multiple organ failure are profound. We investigated whether a mutation in the ATPase subunit-8 gene affects the course of endotoxemic acute liver failure.

Erythropoietin as additive of HTK preservation solution in cold ischemia/reperfusion injury of steatotic livers.

Background: Organ shortage in liver transplantation has justified usage of marginal donor livers to expand the donor organ pool. The particular susceptibility of steatotic livers to I/R injury necessitates optimal preservation conditions in order to minimize preservation-reperfusion injury for successful transplantation.

Methods: The effect of erythropoietin (EPO) as additive to HTK preservation solution was studied in a mouse model.

Uncoupling protein-2 deficient mice are not protected against warm ischemia/reperfusion injury of the liver.

Background: Uncoupling protein-2 (UCP2) might play an important role in mediating ischemia/reperfusion (I/R) injury due to its function in uncoupling of oxidative phosphorylation and in the proton leak-associated increase of reactive oxygen species (ROS) production. The aim of this study was to elucidate the role of UCP2 in hepatic I/R injury.

Materials And Methods: UCP2 wild type and UCP2 deficient mice were subjected to I/R of the left liver lobe.

Darbepoetin-α inhibits the perpetuation of necro-inflammation and delays the progression of cholestatic fibrosis in mice.

Biliary obstruction and cholestasis result in hepatocellular necro-inflammation and lead to the development of liver fibrosis. The objective of this study was to analyze whether the multiple tissue-protective properties of erythropoietin are salutary in an experimental model of liver fibrosis. For this purpose, C57BL/6J mice underwent common bile duct ligation (BDL) and were treated with either darbepoetin-α (10 μg/kg i.

Splenectomy improves survival by increasing arterial blood supply in a rat model of reduced-size liver.

Prevention of acute portal hyperperfusion in small-for-size livers by inflow modulation results in beneficial postoperative outcome. The objective of this study was to unravel the underlying mechanism, emphasizing the intimate relationship between portal venous (PV) and hepatic arterial (HA) blood flow (BF). Rats underwent partial hepatectomy (pHx), splenectomy before pHx or splenectomy and ligation of the A.

Kupffer cell depletion reduces hepatic inflammation and apoptosis but decreases survival in abdominal sepsis.

Objective: During abdominal sepsis, the activation of hepatic Kupffer cells (KC) and its consequences are of central interest. This study evaluates the impact of selective KC depletion on hepatic microcirculation, cytokine release, and systemic alterations in the colon ascendens stent peritonitis (CASP), a model of polymicrobial abdominal sepsis.

Methods: For KC depletion clodronate liposomes were injected 24 h before CASP surgery in female C57BL/6N mice.

Thrombopoietin limits IL-6 release but fails to attenuate liver injury in two hepatic stress models.

Objective: Various pleiotropic substances have been suggested as candidates that directly reduce the severity of liver injury after hepatic ischemia/reperfusion (I/R) and upon acute liver failure (ALF). Herein, we studied whether thrombopoietin (TPO), the main regulator of megakaryopoiesis and thrombopoiesis, showed hepatoprotective effects and might mediate an antiapoptotic function in liver tissue under stress.

Methods/results: In livers with ALF or undergoing warm hepatic I/R, injury was quantified by intravital fluorescence microscopy, chemical, and immunohistochemical analysis as well as western immunoblot.

Role of the perforin/granzyme cell death pathway in D-Gal/LPS-induced inflammatory liver injury.

Cytotoxic T lymphocytes and their granule components, such as perforin and granzyme, play an important role in the defense of hepatic infections caused by different pathogens. Moreover, it has been shown in vitro that hepatocytes can initiate cell death via a perforin-dependent mechanism. Although it is well known that hepatocellular apoptosis in D-galactosamine/lipopolysaccharide (D-Gal/LPS)-associated liver failure is mediated by TNF-alpha-dependent Fas/FasL cytotoxicity, there is no information on the role of perforin-mediated mechanisms in vivo.

Multiple doses of erythropoietin impair liver regeneration by increasing TNF-alpha, the Bax to Bcl-xL ratio and apoptotic cell death.

Background: Liver resection and the use of small-for-size grafts are restricted by the necessity to provide a sufficient amount of functional liver mass. Only few promising strategies to maximize liver regeneration are available. Apart from its erythropoiesis-stimulating effect, erythropoietin (EPO) has meanwhile been recognized as mitogenic, tissue-protective, and anti-apoptotic pleiotropic cytokine.

Uncoupling protein-2 deficiency provides protection in a murine model of endotoxemic acute liver failure.

Objective: Liver injury and cell death are prominent features in the pathogenesis of acute liver failure. Mitochondrial uncoupling protein 2 plays a controversial role in liver cell death through its involvement in the production of reactive oxygen species and adenosine triphosphate.

Design: This randomized controlled animal study was designed to investigate the exact role of uncoupling protein 2 in the pathogenesis of endotoxemic acute liver failure.

H2S contributes to the hepatic arterial buffer response and mediates vasorelaxation of the hepatic artery via activation of K(ATP) channels.

Hepatic blood supply is uniquely regulated by the hepatic arterial buffer response (HABR), counteracting alterations of portal venous blood flow by flow changes of the hepatic artery. Hydrogen sulfide (H(2)S) has been recognized as a novel signaling molecule with vasoactive properties. However, the contribution of H(2)S in mediating the HABR is not yet studied.

Hepatocellular apoptosis is mediated by TNFalpha-dependent Fas/FasLigand cytotoxicity in a murine model of acute liver failure.

There is increasing evidence that the active contribution of hepatocytes to liver disease is strongly dependent on local cytokine environment. It has been shown in vitro that TNFalpha can enhance hepatocyte FasLigand (FasL)-mediated cytotoxicity. Here, we demonstrate that TNFalpha-induced apoptosis was associated with Fas and FasL upregulation and that a FasL-neutralizing antibody prevented TNFalpha-induced apoptosis.

Improved microcirculation by low-viscosity histidine- tryptophan-ketoglutarate graft flush and subsequent cold storage in University of Wisconsin solution: results of an orthotopic rat liver transplantation model.

As previously shown in a model of isolated rat liver perfusion, the combined use of an initial graft flush with low-viscosity histidine-tryptophan-ketoglutarate (HTK) solution followed by cold storage in University of Wisconsin (UW) solution markedly improved the preservation during an extended cold storage period. In this study, we aimed to transfer our results into an in vivo model of orthotopic rat liver transplantation, and to elucidate the potential mechanism of the improved preservation by focusing on the hepatic microcirculation. Livers were harvested from male Wistar rats.

Kupffer cells are mandatory for adequate liver regeneration by mediating hyperperfusion via modulation of vasoactive proteins.

Objective: Physiological liver regeneration requires adequate microvascular perfusion after partial hepatectomy. Although Kupffer cells (KCs) are known to play a key role in modulating hepatocyte proliferation, their impact on regulating hepatic microcirculation during liver regeneration has so far been disregarded. With respect to their expression and modulation of vasoactive mediators, KCs may provide important signals that regulate hepatic perfusion during liver regeneration.

Granulocyte-colony stimulating factor enhances muscle proliferation and strength following skeletal muscle injury in rats.

Insufficiency of skeletal muscle regeneration often impedes the healing process with functional deficiencies and scar formation. We tested the hematopoietic growth factor granulocyte-colony stimulating factor (G-CSF) with respect to its efficacy to improve functional muscle regeneration following skeletal muscle injury in Wistar rats. After crush injury to the left soleus muscle, animals received daily G-CSF (20 mug/kg ip) or vehicle solution (n = 30 per group each).

Local interaction of apoptotic hepatocytes and Kupffer cells in a rat model of systemic endotoxemia.

Aim: There is strong evidence that hepatocellular apoptosis is not only initiated by circulating blood cells which become adherent within the endotoxemic liver, but also contributes to further sustain the inflammatory cell-cell response.

Methods: Because previous studies assumed the importance of the role of cellular cross-talk in mediating inflammatory liver injury, we herein examined the activation of Kupffer cells (KCs) and their spatial coincidence with intrahepatic leukocyte adherence and hepatocellular apoptosis at 6 h after intraperitoneal exposure of rats with lipopolysaccharide (10 mg/kg).

Results: In vivo multifluorescence microscopy revealed liver injury including nutritive perfusion failure, tissue hypoxia, leukocyte accumulation, as well as KC activation and parenchymal apoptotic cell death.

Attenuation of inflammation and apoptosis by pre- and posttreatment of darbepoetin-alpha in acute liver failure of mice.

In many liver disorders inflammation and apoptosis are important pathogenic components, finally leading to acute liver failure. Erythropoietin and its analogues are known to affect the interaction between apoptosis and inflammation in brain, kidney, and myocardium. The present study aimed to determine whether these pleiotropic actions also exert hepatoprotection in a model of acute liver injury.

NO counterbalances HO-1 overexpression-induced acceleration of hepatocyte proliferation in mice.

The trigger for liver regeneration, including shear stress, has been the subject of ongoing debate. Blood vessel-derived gaseous molecules carbon monoxide (CO) and nitric oxide (NO) regulate vascular tone and play an important role in liver regeneration. In heme oxygenase-1 (HO-1) transgenic mice, it has been shown that CO-mediated impairment of vasorelaxation is an NO-dependent event.

Loss of NF-kappaB activation in Kupffer cell-depleted mice impairs liver regeneration after partial hepatectomy.

Kupffer cells (KCs) are located in the liver sinusoids adjacent to hepatocytes and are capable of producing important growth-regulating mediators that exert both stimulatory and inhibitory influences on hepatocyte proliferation by paracrine mechanisms. To elucidate the overall effect of KC depletion on liver regeneration, mice were selectively and long-standing depleted of KCs by liposome-encapsulated dichloromethylene diphosphonate. Using in vivo fluorescence microscopy, immunohistochemistry, Western blot analysis, and NF-kappaB transcription factor DNA binding activity and cytokine assays, we analyzed livers of KC-depleted and KC-competent mice at days 3, 5, and 8 after partial (i.