Matrix metalloproteinase 2 in reduced-size liver transplantation: beyond the matrix.

We studied the contribution of matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9) to the beneficial effects of preconditioning (PC) in reduced-size orthotopic liver transplantation (ROLT). We also examined the role of c-Jun N-terminal kinase (JNK) and whether it regulates MMP2 in these conditions. Animals were subjected to ROLT with or without PC and pharmacological modulation, and liver tissue samples were then analyzed. We found that MMP2, but notMMP9, is involved in the beneficial effects of PC in ROLT. MMP2 reduced hepatic injury and enhanced liver regeneration. Moreover, inhibition of MMP2 in PC reduced animal survival after transplantation. JNK inhibition in the PC group decreased hepatic injury and enhanced liver regeneration. Furthermore, JNK upregulated MMP2 in PC. In addition, we showed that Tissue inhibitors of matrix metalloproteinases 2 (TIMP2) was also upregulated in PC and that JNK modulation also altered its levels in ROLT and PC. Our results open up new possibilities for therapeutic treatments to reduce I/R injury and increase liver regeneration after ROLT, which are the main limitations in living-donor transplantation.

Effects of polyethylene glycol and hydroxyethyl starch in University of Wisconsin preservation solution on human red blood cell aggregation and viscosity.

University of Wisconsin (UW) preservation solution is considered an effective flush and cold storage liquid. However, recent studies have provided evidence of the hyperaggregating effect on human red blood cells (RBC) of hydroxyethyl starch (HES), one of the components of the UW solution. In contrast, preservation solutions containing polyethylene glycol (PEG) have been found to be effective for organ preservation. The aim of this study was to compare the effects of HES (50 g/L); PEG 20 kDa (50 and 30 g/L), and PEG35 kDa (1.05 g/L) added to UW on the rheologic parameters of human RBC at 4 degrees C. Sedimentation rate was measured by the Westergren procedure and blood viscosity evaluated at high shear rates using a cone/plate viscometer. Alterations in RBC morphology and aggregation were evaluated by light microscopy. RBC sedimentation and viscosity were not affected by the inversion of Na+ and K+ concentrations in UW, but were increased by HES. PEGs appeared to reduce RBC deformability with concomitant inhibition of RBC aggregation. These results were consistent with reduced viscosity for PEG-containing solutions. In conclusion, the use of PEG did not change the physiologic function of human RBCs and thus may be an alternative to HES in UW liquids.

[Ischemia-reperfusion syndrome associated with liver transplantation: an update]. / Síndrome de isquemia-reperfusión asociado al trasplante hepático: una visión actualizada.

Ischemia-reperfusion (I/R) injury is the main cause of both initial graft dysfunction and primary failure in liver transplantation. The search for therapeutic strategies to prevent I/R injury has led to research into promising drugs, although most have not been used clinically. Gene therapy requires better transfection techniques, avoiding vector toxicity, and ethical debate before being used clinically. Ischemic preconditioning is the first therapeutic strategy used in clinical practice to reduce I/R injury in hepatectomies for tumors. Future research will provide data on the effectiveness of ischemic preconditioning in reducing I/R injury associated with liver transplantation, and in reducing the vulnerability of steatotic grafts to I/R syndrome so that they can be used in transplantation, thus relieving the organ shortage.

Síndrome de isquemia-reperfusión asociado al trasplante hepático: una visión actualizada / Ischemia-reperfusion syndrome associated with liver transplantation: an update

La lesión por isquemia reperfusión (I/R) es la causa principal tanto del mal funcionamiento inicial del injerto como del fallo primario en el trasplante hepático. La búsqueda de estrategias terapéuticas para prevenir la lesión por I/R ha conducido a la utilización de fármacos esperanzadores, aunque la gran mayoría de ellos no ha alcanzado una aplicación clínica. La terapia génica requiere mejorar las técnicas de transfección, evitar la toxicidad de vectores y una discusión ética antes de alcanzar el nivel clínico. El precondicionamiento isquémico (PC) es la primera estrategia terapéutica utilizada en la clínica para reducir la lesión por I/R en hepatectomías de tumores. Futuras investigaciones aportarán datos acerca de la efectividad del PC para reducir la lesión por I/R asociada al trasplante hepático, y aumentar la poca tolerancia de los injertos esteatósicos al síndrome de I/R para su utilización en el trasplante y aliviar, así, la carencia de órganos

Ischemia-reperfusion (I/R) injury is the main cause of both initial graft dysfunction and primary failure in liver transplantation. The search for therapeutic strategies to prevent I/R injury has led to research into promising drugs, although most have not been used clinically. Gene therapy requires better transfection techniques, avoiding vector toxicity, and ethical debate before being used clinically. Ischemic preconditioning is the first therapeutic strategy used in clinical practice to reduce I/R injury in hepatectomies for tumors. Future research will provide data on the effectiveness of ischemic preconditioning in reducing I/R injury associated with liver transplantation, and in reducing the vulnerability of steatotic grafts to I/R syndrome so that they can be used in transplantation, thus relieving the organ shortage

How ischaemic preconditioning protects small liver grafts.

Interleukin-1 (IL-1) and transforming growth factor-beta (TGFbeta) are key inhibitors of hepatocyte proliferation after hepatectomy. IL-1 inhibition by heat shock proteins (HSPs) has been reported in inflammatory processes. A recent study indicated the benefits of ischaemic preconditioning in reduced-size orthotopic liver transplantation (ROLT). The present study examined: (a) the effect of ischaemic preconditioning on IL-1 and TGFbeta in ROLT; (b) whether preconditioning protects small liver grafts through HSP induction; and (c) whether the potential benefits of preconditioning on HSP is related to IL-1 inhibition. Our results, obtained with an IL-1 receptor antagonist, indicated the injurious effects of IL-1 in ischaemia-reperfusion (I/R) injury and established a relationship between IL-1 and growth factors. Thus, IL-1 reduced hepatocyte growth factor (HGF) and promoted TGFbeta release, thus contributing to the impaired liver regeneration associated with ROLT. Preconditioning inhibited IL-1 through nitric oxide (NO), thereby protecting against the injurious effects of IL-1. In addition, by another pathway independent of NO, preconditioning induced HSP70 and haem-oxygenase-1 (HO-1). HO-1 protected against I/R injury and liver regeneration, whereas the benefits resulting from HSP70 were mainly related to hepatocyte proliferation. These results suggest a mechanism that explains the effectiveness of preconditioning in ROLT. They suggest, too, that other strategies, in addition to preconditioning, that modulate IL-1 and/or HSPs could be considered in clinical situations requiring liver regeneration such as small liver grafts.

Protection of reduced-size liver for transplantation.

The shortage of available organs for liver transplantation has motivated the development of new surgical techniques such as reduced-size liver transplantation. Ischemia-reperfusion (I/R) associated with liver transplantation impairs liver regeneration. Ischemic preconditioning is effective against I/R injury in clinical practice of liver tumour resections. The present study evaluated the effect of ischemic preconditioning on reduced-size liver for transplantation and attempted to identify the underlying protective mechanisms. Hepatic injury and regeneration (transaminases, proliferating cell nuclear antigen [PCNA] labeling index, and hepatocyte growth factor [HGF]) were assessed after reduced-size orthotopic liver transplantation (ROLT). Energy metabolism, oxidative stress, tumor necrosis factor-alpha (TNF) and interleukin-6 (IL-6) were examined as possible mechanisms involved in liver regeneration. Ischemic preconditioning reduced transaminase levels and increased HGF levels and the percentage of PCNA-positive hepatocytes after ROLT. This was associated with a decrease in oxidative stress following ROLT, whereas energy metabolism and hepatic IL-6 and TNF release were unchanged. The benefits of ischemic preconditioning on hepatic injury and liver regeneration could be mediated, at least partially by nitric oxide. These results suggest a new potential application of ischemic preconditioning in reduced-size liver transplantation.