Hepatic Sinusoids Research Articles

Epigenetic Regulation of Kupffer Cell Function in Health and Disease.

Kupffer cells, the resident macrophages of the liver, comprise the largest pool of tissue macrophages in the body. Within the liver sinusoids Kupffer cells perform functions common across many tissue macrophages including response to tissue damage and antigen presentation. They also engage in specialized activities including iron scavenging and the uptake of opsonized particles from the portal blood. Here, we review recent studies of the epigenetic pathways that establish Kupffer cell identity and function. We describe a model by which liver-environment specific signals induce lineage determining transcription factors necessary for differentiation of Kupffer cells from bone-marrow derived monocytes. We conclude by discussing how these lineage determining transcription factors (LDTFs) drive Kupffer cell behavior during both homeostasis and disease, with particular focus on the relevance of Kupffer cell LDTF pathways in the setting of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.

Impaired antibacterial response of liver sinusoidal Vγ9+Vδ2+ T cells in patients with chronic liver disease

ObjectiveThe liver acts as a frontline barrier against diverse gut-derived pathogens, and the sinusoid is the primary site of liver immune surveillance. However, little is known about liver sinusoidal immune...

Non-Cirrhotic Portal Hypertension in a Patient With Colonic Carcinoma Treated With Oxaliplatin

Oxaliplatin is a chemotherapeutic agent with direct toxic action on deoxyribonucleic acid (DNA), which is known to cause an arrest in its synthesis and inducing cell death. It is a crucial medication for colorectal carcinoma, and in combination with other medications has demonstrated to exhibit synergism, managing to increase patients’ survival, especially when compared to monotherapy with 5-fluoracil. Neurotoxicity is its most well-known adverse effect. However, other less frequent secondary effects have been described in case reports, among them liver injury, which is usually secondary to liver sinusoid injury. Despite the wide frequency of the use of this drug, the relationship of oxaliplatin with the development of portal non-cirrhotic hypertension is largely unknown, which translates into a sub-diagnosis, representing an additional risk to patients who develop this complication. We present the case of an adult patient, who during treatment with the FOLFOX scheme for colorectal carcinoma, presents signs suggestive of portal hypertension, without other risk factors besides the administration of oxaliplatin. J Med Cases. 2021;12(3):99-101 doi: https://doi.org/10.14740/jmc3630

Reticuloendothelial activation correlates with disease severity and predicts mortality in severe alcoholic hepatitis.

Overactivation of reticuloendothelial cells lining liver sinusoids - Kupffer cells (macrophages) and sinusoidal endothelial cells - may narrow the sinusoidal lumen, impair perfusion in liver microcirculation and contribute to disease severity in alcoholic hepatitis. The aim of the article was to assess reticuloendothelial activation in patients with severe alcoholic hepatitis (SAH). In SAH patients, we prospectively studied baseline reticuloendothelial activation markers [serum ferritin, sCD163 and plasma von Willebrand factor (VWF) antigen] and Macrophage Activation Syndrome (MAS) criteria, correlated them with disease severity scores [model for end-stage liver disease (MELD) and Sequential Organ Failure Assessment (SOFA) scores] and analyzed their ability to predict survival over a 90-day follow-up period. A total of 50 SAH patients [45 (37-49) years, median (interquartile range), 49 males, discriminant function, 76.2 (54.5-106.6); MELD score, 30 (26.2-36)] were studied. 41 SAH patients (82%) had ferritin >500 ng/mL, and all (100%) had markedly raised sCD163 and VWF levels. The median sCD163 level was 10-fold higher than healthy controls and the median VWF level was 5-fold above the upper limit of normal. In total, 37 SAH patients (74%) met MAS criteria. Reticuloendothelial activation markers correlated with MELD and SOFA scores (P < 0.05). VWF was an independent marker to predict mortality in SAH [adjusted hazard ratio, 1.002 (1.000-1.004)]. The reticuloendothelial system was markedly activated and correlated with disease severity scores in SAH patients.VWF predicted short-term mortality independent of MELD and sCD163. Further larger multicentric studies are needed to validate these findings.

SOME PATHOLOGICAL ASPECTS OF RAW LIMA BEAN (Phaseolus lunatus Linn. FEEDING TO GROWING

Some pathological changes: accompanying raw lima bean (RLB) feeding to growing rats were investigated. Among the gross patholo­gical observations were severe pancreatic hypertrophy and spleen atrophy. The rela­tive weight of the liver was significantly (P&lt; 0M5) decreased while the kidney weight was significantly (P&lt; 0.05) increas­ed. The relative weight of the heart was unaffected. At necropsy, the small intestine of rats fed 40% RLB and aoove were dilated and filed with light-yellow gassy liquid. Histopathologically, livers of rats fed 40% RLB and above showed focuses of coagulative necrosis and marked congestion of hepatic sinusoids and centrolobular veins. The spleen showed marked depletion of lymphoid follicles and medullary' sinu­soids. There was evidence of marked conges­tion of renal blood vessels in the high RLB diets. No lesions were observed in the heart tissues. The morphology of the intestinal apicalmicrovilli were generally disrupted. They appeared stunted and fragmented especially in the rats fed 40% RLB and above. Mononuclei cell infilterate characterized the lamina propria of the small api Large inte­stinal rnicrovilli. No microvilli abnormalities were detected in rats fed 100% cooked lima bean (control) diet.

Protection of liver sinusoids by intravenous administration of human Muse cells in a rat extra-small partial liver transplantation model.

Small‐for‐size syndrome (SFSS) has a poor prognosis due to excessive shear stress and sinusoidal microcirculatory disturbances in the acute phase after living‐donor liver transplantation (LDLT). Multilineage‐differentiating stress enduring (Muse) cells are reparative stem cells found in various tissues and currently under clinical trials. These cells selectively home to damaged sites via the sphingosine‐1‐phosphate (S1P)–S1P receptor 2 system and repair damaged tissue by pleiotropic effects, including tissue protection and damaged/apoptotic cell replacement by differentiating into tissue‐constituent cells. The effects of intravenously administered human bone marrow‐Muse cells and ‐mesenchymal stem cells (MSCs) (4 × 105) on liver sinusoidal endothelial cells (LSECs) were examined in a rat SFSS model without immunosuppression. Compared with MSCs, Muse cells intensively homed to the grafted liver, distributed to the sinusoids and vessels, and delivered improved blood chemistry and Ki‐67(+) proliferative hepatocytes and ‐LSECs within 3 days. Tissue clearing and three‐dimensional imaging by multiphoton laser confocal microscopy revealed maintenance of the sinusoid continuity, organization, and surface area, as well as decreased sinusoid interruption in the Muse group. Small‐interfering RNA‐induced knockdown of hepatocyte growth factor and vascular endothelial growth factor‐A impaired the protective effect of Muse cells on LSECs. Intravenous injection of Muse cells might be a feasible approach for LDLT with less recipient burden.

The potential ameliorative impacts of cerium oxide nanoparticles against fipronil-induced hepatic steatosis

Fipronil (FIP) is a phenylpyrazole insecticide that is commonly used in agricultural and veterinary fields for controlling a wide range of insects, but it is a strong environmentally toxic substance. Exposure to FIP has been reported to increase the hepatic fat accumulation through altered lipid metabolism, which ultimately can contribute to nonalcoholic fatty liver disease (NAFLD) development. The present study aimed to examine the function of cerium oxide nanoparticles (CeNPs) in protecting against hepatotoxicity and lipogenesis induced by FIP. Twenty-eight male albino rats were classified into four groups: FIP (5 mg/kg/day per os), CTR, CeNPs (35 mg/kg/day p.o.), and FIP + CeNPs (5 (FIP) + 35 (CeNPs) mg/kg/day p.o.) for 28 consecutive days. Serum lipid profiles, hepatic antioxidant parameters and pathology, and mRNA expression of adipocytokines were assessed. The results revealed that FIP increased cholesterol, height-density lipoprotein, triacylglyceride, low-density lipoprotein (LDL-c), and very-low-density lipoprotein (VLDL-c) concentrations. It also increased nitric oxide (NO) and malondialdehyde (MDA) hepatic levels and reduced glutathione peroxidase (GPx) and superoxide dismutase (SOD) enzyme activities. Additionally, FIP up-regulated the fatty acid-binding protein (FABP), acetyl Co-A carboxylase (ACC1), and peroxisome proliferator-activated receptor-alpha (PPAR-α). Immunohistochemically, a strong proliferation of cell nuclear antigen (PCNA), ionized calcium-binding adapter molecule 1 (Iba-1), cyclooxygenase-2 (COX-2) reactions in the endothelial cells of the hepatic sinusoids, and increased expression of caspase3 were observed following FIP intoxication. FIP also caused histological changes in hepatic tissue. The CeNPs counteracted the hepatotoxic effect of FIP exposure. So, this study recorded an ameliorative effect of CeNPs against FIP-induced hepatotoxicity.

Lesions caused by Sarcocystis spp., parasites of opossums (Didelphis aurita), in acute and chronic infections in birds (Melopsittacus undulatus).

Protozoa of the genus Sarcocystis are obligatory heterogenous parasites with both definitive and intermediate hosts. Opossums (Didelphis aurita) can shed multiple species of Sarcocystis with birds as the intermediate host. The pathologies of Sarcocystis species in birds have not been thoroughly elucidated. Therefore, the aim of the present study to determine the main lesions that can occur in acute and chronic infections in intermediate hosts, when they ingest infective sporocysts that are shed in the opossum's feces, using budgerigars as a model. To this end, 12 budgerigars, Melopsittacus undulatus, were divided into two groups that received an inoculum with 60 and 120 sporocysts. Birds that died or were euthanized were necropsied, and the lung, tongue, liver, brain, heart, and skeletal striated muscles were collected and fixed in 10% formalin for histopathological analysis. The infectivity varied according to the sample and infective dose. Acute histopathological lesions were characterized by evidence of slightly degenerated hepatocyte cords that permeated the region of the blood vessel and hepatic sinusoids. Pulmonary tissue lesions were also observed in the parabronchial region with the presence of inflammatory infiltrates associated with areas of edema and atelectasis. In chronic infections, few mature cysts were observed in the chest, and many mature cysts in the thigh and tongue muscles. Thus, it was possible to conclude that lesions are highly characteristic in acute infection and, in chronic infections, cysts were present but without major lesions. In this case, the preferred organs of parasitism were the thigh and the tongue.

The morphological specifics of the stromal and parenchymal liver components of 6-12-months old children from hiv-mono-infected mothers

To determine the morphological specifics of the stromal and parenchymal liver components of 6-12-months old children from HIV-mono-infected mothers. Materials and methods. The morphometric investigation included 87 liver tissue biopsies of 6-12-months old dead children from HIV-mono-infected mothers. All morphometric parameters of the parenchymal and stromal liver components were calculated using the Avtandilov`s microscopic morphometric grid, which was consisted of 100 equidistant points. It was inserted into the microscope`s ocular tube with a total × 200 microscope magnification. The number of points that were found on the corresponding types of parenchymal and stromal liver components was calculated. In every case, it was selected 10 random microscopic areas and then all data were obtained, calculated and presented as percentages. Results. Morphometric parameters of hepatocytes: mononuclear hepatocytes – 90.2±7.6 % [control – 93.5±7.1], two-nuclear hepatocytes – 9.8±1.2 % [control – 6.5±1.2], TMHC (two-/mononuclear hepatocytes coefficient) – 0.10±0.02 [control – 0.06±0.01], hepatocytes with fat vacuoles – 19.6±2.1 % [control – 0.5±0.2]. Parenchymal and stromal liver components: parenchyma – 56.1±3.3 % [control – 74.2±4.3], stroma (including blood vessels and bile ducts) – 43.9±3.7 % [control – 25.8±2.6], SPI (stroma/parenchyma index) – 0.78±0.02 [control – 0.34±0.01]. Morphometric parameters of all of the liver components: hepatocytes – 56.1±3.3 % [control – 74.2±4.3], portal tracts – 26.4±2.1 % [control – 3.1±0.6], central veins – 8.1±1.2 % [control – 9.3±1.4], sinusoids – 7.3±1.2 % [control – 10.5±1.3], bile ducts – 2.1±0.1 % [control – 2.9±0.2]. Expression level parameters: fibronectin – 73.2±4.2 % [control – 17.3±2.5], collagen type I – 15.9±1.2 % [control – 9.7±1.9], collagen type III – 20.1±2.6 % [control – 10.1±0.9], collagen type IV – 7.3±0.2 % [control – 5.9±0.2]. Conclusions. It was established, that in the liver of 6-12-months old children from HIV-mono-infected mothers, the parenchymal component of the liver showed the signs of its significant reduction, increase of regenerative activity of hepatocytes, and fatty degeneration of hepatocytes with a certain sign of reactive steatohepatitis. Also, it was established, that the stromal component of the liver of children from HIV-infected mothers showed the signs of its progressive proliferation and collagenization due to increased production and accumulation of fibronectin, type I, type III collagens in the stroma of portal tracts and newly formed septa, and the signs of hepatic sinusoid capillarization due to type IV collagen accumulation in the space of Disse of the hepatic sinusoids.

Imaging Findings and Differential Diagnosis of Hepatic Sinusoidal Occlusion Syndrome and Budd-Chiari Syndrome

Imaging Findings and Differential Diagnosis of Hepatic Sinusoidal Occlusion Syndrome and Budd-Chiari Syndrome

A multipronged approach for the detection of leptospirosis in captive sloth bears (Melursus ursinus) in Agra and Bannerghatta sloth bear rescue centers in India.

Leptospirosis is an exacerbating factor responsible for the drastic decline of sloth bear population in India. In this study, a multipronged approach based on antigen detection using Polymerase Chain Reaction (PCR) employing G1/G2 and LigBF/LigBR primers, antibody detection using Microscopic Agglutination Test (MAT) and recombinant LigBCon1-5 antigen based Latex Agglutination Test (rLigBCon1-5 LAT), serum biochemistry using hepatic (serum glutamate oxalo acetic transaminase (SGOT) and serum glutamate pyruvic transaminase (SGPT) and renal biomarkers (blood urea nitrogen (BUN) and Creatinine) and gross/histopathological evidence in liver and kidneys were employed to investigate leptospirosis in captive sloth bears. A total of 133 serum samples collected from Agra (n=113) and Bannerghatta (n=20) sloth bear rescue centers were screened using MAT and rLigBCon1-5 LAT. A total of 87 and 78 sera tested positive by MAT and LAT respectively. Pyrogenes was the leading serovar obtained using MAT followed by Icterohaemorrhagiae, Javanica, Grippotyphosa, Canicola and Tarassovi. The relative sensitivity, specificity and accuracy of rLigBCon1-5 LAT in comparison to MAT were 89.66%, 100% and 93.23% respectively. PCR performed on hepatic and renal tissues showed amplicon of 285 and 219 base pairs for G1/G2 and LigBF/LigBR primers respectively. Gross evidence (icteric liver, severely engorged hepatic sinusoids, congested kidneys with necrotic white spots on sub capsular surface), histopathology (severe hepatic degeneration and tubulointerstitial nephritis) and elevated hepatic/renal biomarkers were suggestive of leptospirosis. This study suggests that rLigBCon1-5 LAT can be employed as a pen-side test for detecting leptospirosis in sloth bears.

Non-Cirrhotic Portal Hypertension in a Patient With Colonic Carcinoma Treated With Oxaliplatin

Oxaliplatin is a chemotherapeutic agent with direct toxic action on deoxyribonucleic acid (DNA), which is known to cause an arrest in its synthesis and inducing cell death. It is a crucial medication for colorectal carcinoma, and in combination with other medications has demonstrated to exhibit synergism, managing to increase patients’ survival, especially when compared to monotherapy with 5-fluoracil. Neurotoxicity is its most well-known adverse effect. However, other less frequent secondary effects have been described in case reports, among them liver injury, which is usually secondary to liver sinusoid injury. Despite the wide frequency of the use of this drug, the relationship of oxaliplatin with the development of portal non-cirrhotic hypertension is largely unknown, which translates into a sub-diagnosis, representing an additional risk to patients who develop this complication. We present the case of an adult patient, who during treatment with the FOLFOX scheme for colorectal carcinoma, presents signs suggestive of portal hypertension, without other risk factors besides the administration of oxaliplatin.

High Throughput Interrogation of Human Liver Stellate Cells Reveals Microenvironmental Regulation of Phenotype

Liver fibrosis is a common feature of progressive liver disease and is manifested as a dynamic series of alterations in both the biochemical and biophysical properties of the liver. Hepatic stellate cells (HSCs) reside within the perisinusoidal space of the liver sinusoid and are one of the main drivers of liver fibrosis, yet it remains unclear how changes to the sinusoidal microenvironment impact HSC phenotype in the context of liver fibrosis. Cellular microarrays were used to examine and deconstruct the impacts of bio-chemo-mechanical changes on activated HSCs in vitro . Extracellular matrix (ECM) composition and stiffness were found to act individually and in combination to regulate HSC fibrogenic phenotype and proliferation. Hyaluronic acid and collagen III promoted elevated collagen I expression while collagen IV mediated a decrease. HSCs exhibited reduced lysyl oxidase (Lox) expression as stiffness increased, with less dependence on ECM composition. Collagens III and IV had positive impacts on HSC proliferation, whereas hyaluronic acid had the opposite effect. Meta-analysis performed on these data revealed distinct phenotypic clusters (e.g. low fibrogenesis/high proliferation) as a direct function of their microenvironmental composition. Notably, soft microenvironments mimicking healthy tissue (1 kPa), promoted higher levels of intracellular collagen I and Lox expression in activated HSCs, compared to stiff microenvironments mimicking fibrotic tissue (25 kPa). Collectively, these data suggest potential HSC functional adaptations in response to specific bio-chemo-mechanical changes relevant relevant towards the development of therapeutic interventions. These findings also underscore the importance of the microenvironment when interrogating HSC behavior in healthy, disease, and treatment settings.

MAdCAM-1/α4β7 Integrin-Mediated Lymphocyte/Endothelium Interactions Exacerbate Acute Immune-Mediated Hepatitis in Mice.

Background & AimsAberrant lymphocyte homing could potentially link inflammatory processes in the intestine and the liver, as distinct hepatobiliary diseases frequently develop as extra-intestinal manifestations in inflammatory bowel disease. In this study, we examined the role of the gut-tropic leukocyte adhesion molecule β7 integrin and its endothelial ligand mucosal addressin cell-adhesion molecule-1 (MAdCAM-1) in immune-mediated hepatitis in mice.MethodsWild-type (WT) mice, MAdCAM-1-deficient mice, β7 integrin-deficient mice, RAG-2–deficient mice, RAG-2/MAdCAM-1 double-deficient mice, and RAG-2/β7 integrin double-deficient mice were subjected to concanavalin A (ConA)-induced hepatitis. The degree of hepatitis was evaluated by histology, flow cytometry, and expression analysis of inflammatory mediators. The motility of lymphocytes in progressive liver damage was assessed by intravital laser scanning multiphoton microscopy.ResultsAblation of MAdCAM-1 or β7 integrin ameliorated ConA-induced hepatitis in mice. β7 integrin-deficient lymphocytes caused less liver damage than WT lymphocytes in ConA-treated RAG-2–deficient mice. Moreover, WT lymphocytes caused less liver damage in ConA-treated RAG-2/β7 integrin double-deficient mice than in similarly treated RAG-2–deficient mice, indicating that β7 integrin expression contributes significantly to the liver damage mediated by innate immune cells. MAdCAM-1 expression was dependent on β7 integrin expression on adaptive and innate immune cells. Most importantly, lymphocytes in ConA-treated MAdCAM-1-deficient mice displayed more motility and less adhesion in the liver sinusoids in vivo, than lymphocytes in similarly treated WT mice.ConclusionsThese data suggest that β7 integrin expression on lymphocytes and innate immune cells contributes to MAdCAM-1 upregulation and liver damage in acute immune-mediated hepatitis, most likely by facilitating lymphocyte/sinusoidal endothelial cell interactions.

Role of Natural Killer Cells in Uveal Melanoma.

Simple SummaryMetastatic Uveal Melanoma (MUM) is a lethal malignancy with no durable treatment available to date. A vast majority of patients with MUM present with liver metastasis. The liver harbors metastatic disease with an apparent lack of a cytotoxic T cell response. It is becoming evident that MUM is not an immunologically silent malignancy and the investigation of non-T cell anti-tumor immunity is warranted. In this review, we highlight the relevance of Natural Killer (NK) cells in the biology and treatment of MUM. Potent anti-NK cell immunosuppression employed by uveal melanoma alludes to its vulnerability to NK cell cytotoxicity. On the contrary, micro-metastasis in the liver survive for several years within close vicinity of a plethora of circulating and liver-resident NK cells. This review provides unique perspectives into the potential role of NK cells in control or progression of uveal melanoma.Uveal melanoma has a high mortality rate following metastasis to the liver. Despite advances in systemic immune therapy, treatment of metastatic uveal melanoma (MUM) has failed to achieve long term durable responses. Barriers to success with immune therapy include the immune regulatory nature of uveal melanoma as well as the immune tolerant environment of the liver. To adequately harness the anti-tumor potential of the immune system, non-T cell-based approaches need to be explored. Natural Killer (NK) cells possess potent ability to target tumor cells via innate and adaptive responses. In this review, we discuss evidence that highlights the role of NK cell surveillance and targeting of uveal melanoma. We also discuss the repertoire of intra-hepatic NK cells. The human liver has a vast and diverse lymphoid population and NK cells comprise 50% of the hepatic lymphocytes. Hepatic NK cells share a common niche with uveal melanoma micro-metastasis within the liver sinusoids. It is, therefore, crucial to understand and investigate the role of intra-hepatic NK cells in the control or progression of MUM.

Transcriptome and proteome profiling reveal complementary scavenger and immune features of rat liver sinusoidal endothelial cells and liver macrophages

BackgroundLiver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs; liver resident macrophages) form the body’s most effective scavenger cell system for the removal of harmful blood-borne substances, ranging from modified self-proteins to pathogens and xenobiotics. Controversies in the literature regarding the LSEC phenotype pose a challenge when determining distinct functionalities of KCs and LSECs. This may be due to overlapping functions of the two cells, insufficient purification and/or identification of the cells, rapid dedifferentiation of LSECs in vitro, or species differences. We therefore characterized and quantitatively compared expressed gene products of freshly isolated, highly pure LSECs (fenestrated SE-1/FcγRIIb2+) and KCs (CD11b/c+) from Sprague Dawley, Crl:CD (SD), male rats using high throughput mRNA-sequencing and label-free proteomics.ResultsWe observed a robust correlation between the proteomes and transcriptomes of the two cell types. Integrative analysis of the global molecular profile demonstrated the immunological aspects of LSECs. The constitutive expression of several immune genes and corresponding proteins of LSECs bore some resemblance with the expression in macrophages. LSECs and KCs both expressed high levels of scavenger receptors (SR) and C-type lectins. Equivalent expression of SR-A1 (Msr1), mannose receptor (Mrc1), SR-B1 (Scarb1), and SR-B3 (Scarb2) suggested functional similarity between the two cell types, while functional distinction between the cells was evidenced by LSEC-specific expression of the SRs stabilin-1 (Stab1) and stabilin-2 (Stab2), and the C-type lectins LSECtin (Clec4g) and DC-SIGNR (Clec4m). Many immune regulatory factors were differentially expressed in LSECs and KCs, with one cell predominantly expressing a specific cytokine/chemokine and the other cell the cognate receptor, illustrating the complex cytokine milieu of the sinusoids. Both cells expressed genes and proteins involved in antigen processing and presentation, and lymphocyte co-stimulation.ConclusionsOur findings support complementary and partly overlapping scavenging and immune functions of LSECs and KCs. This highlights the importance of including LSECs in studies of liver immunity, and liver clearance and toxicity of large molecule drugs and nano-formulations.

Hepatic sinusoids versus central veins: Structures, markers, angiocrines, and roles in liver regeneration and homeostasis.

The blood circulates through the hepatic sinusoids delivering nutrients and oxygen to the liver parenchyma and drains into the hepatic central vein, yet the structures and phenotypes of these vessels are distinctively different. Sinusoidal endothelial cells are uniquely fenestrated, lack basal lamina and possess organelles involved in endocytosis, pinocytosis, degradation, synthesis and secretion. Hepatic central veins are nonfenestrated but are also active in synthesis and secretion. Endothelial cells of sinusoids and central veins secrete angiocrines that play respective roles in hepatic regeneration and metabolic homeostasis. The list of markers for identifying sinusoidal endothelial cells is long and their terminologies are complex. Further, their uses vary in different investigations and, in some instances, could be confusing. Central vein markers are fewer but more distinctive. Here we analyze and categorize the molecular pathways/modules associated with the sinusoid-mediated liver regeneration in response to partial hepatectomy and chemical-induced acute or chronic injury. Similarly, we highlight the findings that central vein-derived angiocrines interact with Wnt/β-catenin in perivenous hepatocytes to direct gene expression and maintain pericentral metabolic zonation. The proposal that perivenous hepatocytes behave as stem/progenitor cells to provoke hepatic homeostatic cell renewal is reevaluated and newer concepts of broad zonal distribution of hepatocyte proliferation in liver homeostasis and regeneration are updated. Thus, this review integrates the structures, biology and physiology of liver sinusoids and central veins in mediating hepatic regeneration and metabolic homeostasis.

Hepatotoxicity of the anionic surfactant linear alkylbenzene sulphonate (LAS) in bullfrog tadpoles

The liver of anurans play an important role in metabolism, including detoxification, the biotransformation of molecules, and the storage of metabolites. Surfactants are part of domestic and industrial effluents. The effects of linear alkylbenzene sulfonate (LAS) on anuran liver remain unknown, however, some studies have evaluated the effects of LAS on the skin, gills, heart, testes, and liver of fishes. Here, we tested the hypothesis that LAS is hepatotoxic, promoting morphometric alterations in hepatocytes along with inflammation in the tissue, altering hepatic catabolism. We evaluated the effects of a LAS concentration that is considered environmentally safe in Brazilian inland waters on the liver of Lithobates catesbeianus tadpoles, including studies on morphology, morphometry, immunology, and metabolism. LAS exposure promoted enlargement of liver sinusoids and vacuolization of hepatocytes. Exposure to LAS also increased the area of mast cells and melanomacrophages (MMs). Additionally, LAS exposure increased hemosiderin inside MMs, suggesting alterations in the catabolism and storage of iron. Hepatocyte size increased after exposure to LAS, suggesting cytotoxic effects. Integrative analyses (i.e., morphometric, metabolic, and immunological) demonstrated hepatotoxic effects of LAS. These types of studies are key to understanding the negative effects of these substances on tadpole health, as these liver alterations impair anuran homeostasis.

Prognosis of primary hepatic lymphoma: A US population-based analysis

ObjectivePrimary hepatic lymphoma (PHL) is a rare malignancy with lesions confined to the liver. It is characterized by a large number of monomorphic, medium-sized lymphocytic infiltrates in the hepatic sinusoid. Due to the rarity of this malignancy, our current understanding of PHL is limited. MethodsWe collected incidence, mortality, and clinical data of PHL patients diagnosed between 1975 and 2016 using the Surveillance, Epidemiology, and End Results (SEER) database. The annual percentage changes (APCs) and prognoses were analyzed using the Joinpoint and R package. ResultsAmong the 1,372 patients, white males were prevalent, and the most common histological subtype was diffuse large B-cell lymphoma (DLBCL). The incidence and mortality rate of PHL was 0.075/100,000 person-years and 0.055/100,000 person-years, respectively. The annual incidence rate of PHL increased significantly, with an APC of 2.74% (P < 0.001). The 3- and 5-year overall survival (OS) rates of patients with PHL were 43.553% and 39.242%, respectively. The 3- and 5-year relative survival (RS) rates were 46.925% and 45.300%, respectively. Multivariate Cox regression analysis revealed that older age, black, DLBCL, and advanced-stage disease were independent predictors of unfavorable OS and RS. The C-index and receiver operating characteristic (ROC) analysis confirmed the prognostic value of the nomograms established in this study. ConclusionThe nomogram established in this study is a robust tool to predict the prognosis of PHL patients.

Nonalcoholic fatty liver disease (NAFLD) severity is associated to a nonhemostatic contribution and proinflammatory phenotype of platelets

Nonalcoholic fatty liver disease (NAFLD) is the main cause of chronic liver disease and ranges from simple steatosis to nonalcoholic steatohepatitis. Recently, a platelet role in NAFLD pathogenesis and progression has been reported in mouse models and in patients. We investigated whether platelets are involved in liver and systemic inflammation processes in NAFLD. In this exploratory study we recruited 24 consecutive patients with biopsy-proven diagnosis of NAFLD and 17 healthy volunteers. We measured plasma levels of inflammatory markers by ELISA. We investigated hemostatic and inflammatory transcripts in circulating platelets and leukocytes from NAFLD patients. We analyzed platelet and neutrophil extracellular traps (NET) accumulations in liver sinusoids using CD42 and H3 citrullinated histones immunohistochemical staining on liver biopsies. NAFLD patients had increased inflammation markers and lipolysaccharides plasma levels. We found significant increase of inflammatory transcripts in circulating platelets and not in leukocytes of NAFLD subjects compared with healthy controls. We demonstrated increased intrahepatic platelet accumulation that correlated with NAFLD activity score (NAS) score and intrahepatic neutrophil extracellular traps (NET) formation in liver biopsies of NAFLD patients. NET formation was higher in livers with higher NAS and inflammation scores. The presence of low-grade systemic inflammation and proinflammatory changes of circulating platelets indicate that platelets participate on systemic inflammatory changes associated with NAFLD. Liver platelet accumulation and liver NET formation, together with low-grade endotoxemia, suggest that platelets may act to protect the liver from invading microorganisms by favoring local NET formation.