The Hepatic Sinusoid in Chronic Liver Disease: The Optimal Milieu for Cancer

The liver sinusoids are a unique type of microvascular beds. The specialized phenotype of sinusoidal cells is essential for their communication, and for the function of all hepatic cell types, including hepatocytes. Liver sinusoidal endothelial cells (LSECs) conform the inner layer of the sinusoids, which is permeable due to the fenestrae across the cytoplasm; hepatic stellate cells (HSCs) surround LSECs, regulate the vascular tone, and synthetize the extracellular matrix, and Kupffer cells (KCs) are the liver-resident macrophages. Upon injury, the harmonic equilibrium in sinusoidal communication is disrupted, leading to phenotypic alterations that may affect the function of the whole liver if the damage persists. Understanding how the specialized sinusoidal cells work in coordination with each other in healthy livers and chronic liver disease is of the utmost importance for the discovery of new therapeutic targets and the design of novel pharmacological strategies. In this manuscript, we summarize the current knowledge on the role of sinusoidal cells and their communication both in health and chronic liver diseases, and their potential pharmacologic modulation. Finally, we discuss how alterations occurring during chronic injury may contribute to the development of hepatocellular carcinoma, which is usually developed in the background of chronic liver disease.

CCL25 mediates inflammatory crosstalk between adipose and liver in non-alcoholic fatty liver disease

Background and Aims: Obesity is closely associated with non-alcoholic fatty liver disease (NAFLD). We investigated expression of the CC-chemokine CCL25 in adipose tissue (AT) and its relation to hepatic inflammation. Methods: Primary human tissue was used for all experiments. CCL25 concentration in serum was measured with enzyme-linked immunosorbent assay (ELISA). Gene expression of CCL25 was measured with polymerase chain reaction. Protein expression was assessed with ELISA and immunohistochemistry. Leukocyte trafficking was investigated in a dynamic assay to model the hepatic sinusoid. Expression of CCR9 on liver-infiltrating leukocytes analysed with flow cytometry. Results: Circulating CCL25 was increased in obesity. Gene expression of CCL25 in AT was several-fold higher than in liver, although protein levels of CCL25 were comparable. Soluble CCL25 in flow media increased leukocyte trafficking across hepatic endothelium. Greater numbers of CCR9+ cells were seen in liver tissue from patients with NAFLD, where the greatest difference was in the number of CD14+CD16+ monocytes. Conclusions: CCL25 and its cognate receptor CCR9 mediate a novel pathway of inflammatory crosstalk between adipose and liver tissue in NAFLD.

Effects of Tamiflu and Adamine on histology and ultrastructure of the liver of albino mice

Background Tamiflu (Oseltamivir) and Adamine (Amantadine HCl) are antiviral drugs which are used for prevention and treatment for influenza. The present study was carried out to evaluate the effect of Tamiflu and Adamine on the liver of adult male albino mice from the histological and ultrastructural points of views. Results Histological examination of liver sections treated with Tamiflu and Adamine included enlargement and congestion of central and hepatic veins in addition to erosion of their endothelial lining cells, cytoplasmic vacuolation of hepatocytes, pyknosis of their nuclei, and dilatation of hepatic sinusoid. The electron microscopic investigation illustrated mitochondrial swelling, fragmented rough endoplasmic reticulum, cytoplasmic vacuolation, the nuclei with irregular envelope and condensed heterochromatin, dilated microvilli in sinusoid, in addition to active Kupffer cells have many lysosomes and filopodia in its membrane. Conclusion The study suggested that both drugs induced histopathological and ultrastructural alterations in hepatic tissue. In conclusion, Tamiflu and Adamine have pathological effects on liver of albino mice (Mus musculus).

Anti-CD321 antibody immunotherapy protects liver against ischemia and reperfusion-induced injury

The prognosis of the liver transplant patients was frequently deteriorated by ischemia and reperfusion injury (IRI) in the liver. Infiltration of inflammatory cells is reported to play critical roles in the pathogenesis of hepatic IRI. Although T lymphocytes, neutrophils and monocytes infiltrated into the liver underwent IRI, we found that neutrophil depletion significantly attenuated the injury and serum liver enzyme levels in a murine model. Interestingly, the expression of CD321/JAM-A/F11R, one of essential molecules for transmigration of circulating leukocytes into inflammatory tissues, was significantly augmented on hepatic sinusoid endothelium at 1 h after ischemia and maintained until 45 min after reperfusion. The intraportal administration of anti-CD321 monoclonal antibody (90G4) significantly inhibited the leukocytes infiltration after reperfusion and diminished the damage responses by hepatic IRI (serum liver enzymes, inflammatory cytokines and hepatocyte cell death). Taken together, presented results demonstrated that blockade of CD321 by 90G4 antibody significantly attenuated hepatic IRI accompanied with substantial inhibition of leukocytes infiltration, particularly inhibition of neutrophil infiltration in the early phase of reperfusion. Thus, our work offers a potent therapeutic target, CD321, for preventing liver IRI.

Hepatosplenic T-cell lymphoma with hepatocytotropism in a cat

Case summary A 14-year 3-month-old spayed female mixed-breed cat presented with jaundice, anaemia and thrombocytopenia. Haemophagocytic syndrome associated with lymphoma was suspected after cytological examination of the spleen. Despite treatment with prednisolone, L-asparaginase and nimustine, the cat died 176 days after the initial presentation. Necropsy revealed splenomegaly and hepatomegaly, without lymphadenopathy. Histopathologically, neoplastic lymphoid cells infiltrated the hepatic sinusoid and splenic sinus. The neoplastic lymphoid cells showed marked hepatocytotropism and contained erythrocytes, which was also confirmed by electron microscopy. Immunohistochemically, neoplastic lymphoid cells were positive for CD3, TIA1 (GMP-17) and granzyme B, and negative for CD8, CD20, CD56, CD57, CD79a and Iba1. Based on these findings, the cat was diagnosed with hepatosplenic T-cell lymphoma (HS-TCL) with hepatocytotropism. Relevance and novel information This case shows cytotoxic immunophenotype of HS-TCL in a cat, which has not been demonstrated before. Severe hepatocytotropism and haemophagocytosis of the neoplastic cells were likely to be associated with jaundice and anaemia, respectively, and the poor outcome of the present case.

Aging and Chronic Liver Disease

Aging increases the incidence of chronic liver disease (CLD), worsens its prognosis, and represents the predominant risk factor for its development at all different stages. The hepatic sinusoid, which is fundamental for maintaining liver homeostasis, is composed by hepatocytes, liver sinusoidal endothelial cells, hepatic stellate cells, and hepatic macrophages. During CLD progression, hepatic cells suffer deregulations in their phenotype, which ultimately lead to disease development. The effects of aging on the hepatic sinusoid phenotype and function are not well understood, nevertheless, studies performed in experimental models of liver diseases and aging demonstrate alterations in all hepatic sinusoidal cells. This review provides an updated description of age-related changes in the hepatic sinusoid and discusses the implications for CLD development and treatment. Lastly, we propose aging as a novel therapeutic target to treat liver diseases and summarize the most promising therapies to prevent or improve CLD and extend healthspan.