Ischemic Preconditioning Directly or Remotely Applied on the Liver to Reduce Ischemia-Reperfusion Injury in Resections and Transplantation

Ischemia-reperfusion (I/R) injury is an important cause of liver damage occurring during surgical procedures. In liver resection, I/R causes post-operative transaminasemia and liver function failure. In liver transplantation, I/R causes graft dysfunction, ranging from biochemical abnormalities to primary non-function of the transplanted organ. Ischemic preconditioning is a surgical strategy to reduce the severity of I/R and improve post-operative outcomes by prior exposure to a brief period of vascular occlusion directly to the target organ or remotely to a distant vascular bed. This chapter aims to discuss the different ischemic preconditioning strategies in both liver resection surgery and liver transplantation. In addition, we will describe the differences of such surgical strategies in both steatotic and non-steatotic livers in both preclinical experiments and clinical practice. Such information may be useful to guide the design of the effective ischemic preconditioning methods in the surgery of hepatic resections and liver transplantation

Emerging Therapeutic Targets for Portal Hypertension.

PURPOSE OF REVIEW Portal hypertension is responsible of the main complications of cirrhosis, which carries a high mortality. Recent treatments have improved prognosis, but this is still far from ideal. This paper reviews new potential therapeutic targets unveiled by advances of key pathophysiologic processes. RECENT FINDINGS Recent research highlighted the importance of suppressing etiologic factors and a safe lifestyle and outlined new mechanisms modulating portal pressure. These include intrahepatic abnormalities linked to inflammation, fibrogenesis, vascular occlusion, parenchymal extinction, and angiogenesis; impaired regeneration; increased hepatic vascular tone due to sinusoidal endothelial dysfunction with insufficient NO availability; and paracrine liver cell crosstalk. Moreover, pathways such as the gut-liver axis modulate splanchnic vasodilatation and systemic inflammation, exacerbate liver fibrosis, and are being targeted by therapy. We have summarized studies of new agents addressing these targets. SUMMARY New agents, alone or in combination, allow acting in complementary mechanisms offering a more profound effect on portal hypertension while simultaneously limiting disease progression and favoring regression of fibrosis and of cirrhosis. Major changes in treatment paradigms are anticipated

Hepatic Regeneration Under Warm or Cold Ischemia Conditions: Controversies and New Approaches

Ischemia-reperfusion (I/R) associated with hepatic resection and living related liver transplantation is an unsolved problem in clinical practice. Indeed, I/R induces damage and regenerative failure in clinical liver surgery. Signaling pathways regarding the pathophysiology of liver I/R and regeneration making clear distinction between situations of cold and warm ischemia, as well as liver regeneration with or without vascular occlusion, will be addressed. The different experimental models used to date to improve the postoperative outcomes in clinical liver surgery will be also described. Furthermore, the most updated therapeutic strategies, as well as the clinical and scientific controversies in the field, will be discussed. Such information may be useful to guide the design of better experimental models as well as the effective therapeutic strategies in liver surgery that can succeed in achieving its clinical application

Endoplasmic Reticulum and Mitochondria Contacts Correlate with the Presence and Severity of NASH in Humans.

The interaction between the mitochondria and the endoplasmic reticulum (ER) is essential for hepatocyte function. An increase in ER-mitochondria contacts (ERMCs) is associated with various metabolic diseases. Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and type 2 diabetes, and its progressive form non-alcoholic steatohepatitis (NASH) can lead to cirrhosis and hepatocellular carcinoma. However, the role of ERMCs in the progression of NAFL to NASH is still unclear. We assessed whether ERMCs could correlate with NAFLD severity. We used a proximity ligation assay to measure the abundance of ERMCs in liver biopsies from patients with biopsy-proven NAFLD (n = 48) and correlated the results with histological and metabolic syndrome (MetS) features. NAFLD patients were included according to inclusion and exclusion criteria, and then assigned to NAFL (n = 9) and NASH (n = 39) groups. ERMCs density could discriminate NASH from NAFL (sensitivity 61.5%, specificity 100%). ERMCs abundance correlated with hepatocellular ballooning. Moreover, the density of ERMCs increased with an increase in the number of MetS features. In conclusion, ERMCs increased from NAFL to NASH, in parallel with the number of MetS features, supporting a role for this interaction in the pathophysiology of NASH

New Perspectives on the Use of Sub-Optimal Donor Livers

Liver transplantation is the therapy of choice for patients with end-stage liver disease. However, a shortage of donor organs remains a major obstacle to the widespread application of liver transplantation. To overcome this problem, transplant centers have developed strategies to expand the organ donor pool, including the routine use of sub-optimal donor livers. However, these have an increased risk of initial poor function or primary non-function that may cause greater risk of morbidity in the recipient. This chapter aims to describe the pathophysiological changes that may occur in sub-optimal donor livers, focusing on viral infections, since, after transplantation, infection of the graft is almost universal and can lead to chronic hepatitis, cirrhosis, and graft failure. The different experimental models as well as the clinical outcomes of the transplantation of sub-optimal donor livers with viral infections will be discussed. Such information may be useful to guide the design of better experimental models than those described to date as well as the effective use of sub-optimal livers with successful clinical application

Animal models for liver disease – A practical approach for translational research

Animal models are crucial for improving our understanding of human pathogenesis, enabling researchers to identify therapeutic targets and test novel drugs. In the current review, we provide a comprehensive summary of the most widely used experimental models of chronic liver disease, starting from early stages of fatty liver disease (non-alcoholic and alcoholic) to steatohepatitis, advanced cirrhosis and end-stage primary liver cancer. We focus on aspects such as reproducibility and practicality, discussing the advantages and weaknesses of available models for researchers who are planning to perform animal studies in the near future. Additionally, we summarise current and prospective models based on human tissue bioengineering

Review: Vascular effects of PPARs in the context of NASH.

BACKGROUND Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors known to regulate glucose and fatty acid metabolism, inflammation, endothelial function and fibrosis. PPAR isoforms have been extensively studied in metabolic diseases, including type 2 diabetes and cardiovascular diseases. Recent data extend the key role of PPARs to liver diseases coursing with vascular dysfunction, including nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). AIM This review summarises and discusses the pathobiological role of PPARs in cardiovascular diseases with a special focus on their impact and therapeutic potential in NAFLD and NASH. RESULTS AND CONCLUSIONS PPARs may be attractive for the treatment of NASH due to their liver-specific effects but also because of their efficacy in improving cardiovascular outcomes, which may later impact liver disease. Assessment of cardiovascular disease in the context of NASH trials is, therefore, of the utmost importance, both from a safety and efficacy perspective

Improved hemodynamic and liver function in portal hypertensive cirrhotic rats after administration of B. pseudocatenulatum CECT 7765

Purpose: Evaluating whether changes in gut microbiota induced by a bifidobacterial strain may have an effect on the hepatic vascular function in portal hypertensive cirrhotic rats.Methods: Bile duct ligation (BDL) was performed in rats. A subgroup of animals received B. pseudocatenulatum CECT7765 (109 cfu/daily ig.) for 1 week prior to laparotomy. Hemodynamic, biochemical and inflammatory markers were evaluated. Ileal microbiota composition was identified. Statistical analysis was performed.Results: Sham-operated (n = 6), BDL (n = 6) and BDL treated with bifidobacteria (n = 8) rats were included. B. pseudocatenulatum CECT7765 significantly decreased proteobacteria (p = 0.001) and increased Bacteroidetes (p = 0.001) relative abundance. The bifidobacteria decreased the Firmicutes/Bacteroidetes ratio in the BDL model (p = 0.03). BDL with bifidobacteria vs BDL rats showed: significantly reduced portal vein area, portal flow, congestion index, alkaline phosphatase and total bilirubin, significantly increased serum cytokines and nitric oxide levels, gene expression levels of bile acids receptor FXR and endothelial nitric oxide synthase. Quantitative changes in the Clostridiales and Bacteroidales orders were independently associated with variations in portal vein area and portal flow, while changes in the Proteobacteria phylum were independently associated with congestion. Variations in all liver function markers significantly correlated with total OTUs mainly in the Firmicutes, but only changes in the Clostridiales were independently associated with alkaline phosphatase in the ANCOVA analysis.Conclusion: Hemodynamic alterations and liver dysfunction induced by BDL in rats are partially restored after oral administration of B. pseudocatenulatum CECT7765. Results provide a proof-of-concept for the beneficial effect of this bifidobacterial strain in reducing complications derived from portal hypertension in cirrhosis