Search

To investigate the relationship between the intrahepatic expression of podoplanin (PDPN) and Kupffer cells (KCs) in ischemia–reperfusion (I/R) liver damage. C57Bl/6 mice were injected with 200 µl of clodronate liposomes (macrophage depletion; MDP group) to deplete KCs or control liposomes (control group) via the ophthalmic vein plexus 24 h prior to ischemia. Animals were subjected to 90 min of partial hepatic ischemia (70%), followed by reperfusion, and were then killed at designated time points. Serum and liver tissues were harvested for further analyses. Serum ALT levels, mortality rates, and the percentage of necrotic area in liver sections were significantly higher in the MDP group than in the control group. PDPN was expressed in the lymphatic epithelium, interlobular bile duct epithelium, and in some hepatocytes in each group. Its expression in hepatocytes was down-regulated in the MDP group. The accumulation of platelets in the sinusoid was reduced 6 h after I/R in the MDP group. Tissue HGF and IGF-1 levels decreased in the MDP group. These results suggest that KCs play a key role in the activation of platelets through direct contact with PDPN-positive hepatocytes in I/R livers.

Purpose Erectile dysfunction (ED) is one of the increasing diseases with aging society. The basis of ED derived from local penile abnormality is poorly understood because of the complex three‐dimensional (3D) distribution of sinusoids in corpus cavernosum (CC). Understanding the 3D histological structure of penis is thus necessary. Analyses on the status of regulatory signals for such abnormality are also performed. Methods To analyze the 3D structure of sinusoid, 3D reconstruction from serial sections of murine CC were performed. Histological analyses between young (2 months old) and aged (14 months old) CC were performed. As for chondrogenic signaling status of aged CC, SOX9 and RBPJK staining was examined. Results Sinusoids prominently developed in the outer regions of CC adjacent to tunica albuginea. Aged CC samples contained ectopic chondrocytes in such regions. Associating with the appearance of chondrocytes, the expression of SOX9, chondrogenic regulator, was upregulated. The expression of RBPJK, one of the Notch signal regulators, was downregulated in the aged CC. Conclusions Prominent sinusoids distribute in the outer region of CC which may possess important roles for erection. A possibility of ectopic chondrogenesis induced by alteration of SOX9/Notch signaling with aging is indicated.

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 cells in the context of chronic liver disease (CLD). Here, we investigated the antibacterial capacity of liver sinusoidal γδ T cells in patients with various CLDs.DesignWe analysed the frequency, phenotype and functions of human liver sinusoidal γδ T cells from healthy donors and recipients with CLD, including HBV-related CLD (liver cirrhosis (LC) and/or hepatocellular carcinoma (HCC)), alcoholic LC and LC or HCC of other aetiologies, by flow cytometry and RNA-sequencing using liver perfusates obtained during living donor liver transplantation. We also measured the plasma levels of D-lactate and bacterial endotoxin to evaluate bacterial translocation.ResultsThe frequency of liver sinusoidal Vγ9+Vδ2+ T cells was reduced in patients with CLD. Immunophenotypic and transcriptomic analyses revealed that liver sinusoidal Vγ9+Vδ2+ T cells from patients with CLD were persistently activated and pro-apoptotic. In addition, liver sinusoidal Vγ9+Vδ2+ T cells from patients with CLD showed significantly decreased interferon (IFN)-γ production following stimulation with bacterial metabolites and Escherichia coli. The antibacterial IFN-γ response of liver sinusoidal Vγ9+Vδ2+ T cells significantly correlated with liver function, and inversely correlated with the plasma level of D-lactate in patients with CLD. Repetitive in vitro stimulation with E. coli induced activation, apoptosis and functional impairment of liver sinusoidal Vγ9+Vδ2+ T cells.ConclusionLiver sinusoidal Vγ9+Vδ2+ T cells are functionally impaired in patients with CLD. Bacterial translocation and decreasing liver functions are associated with functional impairment of liver sinusoidal Vγ9+Vδ2+ T cells.

The aim of this study was to develop a hemostatic agent with anti-adhesive properties and to study its effect on liver morphology, metabolic activity and hepatocyte regeneration in experimental liver injury. Methods. In 60 rats following experimental resection liver injury, the time of bleeding and the volume of blood loss were determined. Histological preparations were used to study the size of hepatocytes and their nuclei, the content of glycogen (PAS-reaction), the number of binucleated hepatocytes and the expression of Ki-67. Results. Compared with the control, an agent based on 6% sodium carboxymethylcellulose gel and 5% aminocaproic acid effectively and reliably reduces the bleeding time by 72% (217.91 s), the volume of blood loss by 74.7% (372.85 mg) (p ≤ 0.01) and the degree of blood filling of the sinusoid liver capillaries. In addition, the use of the novel gel prevents the adhesion formation. It stimulates mitotic activity of hepatocytes, accompanied by an increase in the number of binucleated hepatocytes and Ki-67 expression. By the 14th day, this activity significantly decreases. Hypertrophy of hepatocytes and their nuclei is observed by the 7th and 14th days of the experiment. This indicates both an increase in the metabolic activity of hepatocytes and intracellular regeneration. The use of the hemostatic gel does not alter the glycogen-storing function of hepatocytes, which indicates the lack of pronounced hypoxia due to effective control of bleeding. Conclusion. The local hemostatic gel based on 6% sodium carboxymethylcellulose gel and 5% aminocaproic acid can be recommended for local bleeding control in liver injuries and surgery.

ObjectivesTo describe the histopathologic and immunophenotypic features of a temporary splenic allograft exposed to massive donor-specific antibody (DSA) insult.MethodsA human cadaveric donor splenic allograft was temporarily transplanted in a highly sensitized patient with the intention of removing DSA before intestinal transplantation from the same donor. Before splenic transplant, the patient had several preformed cytotoxic DSAs that resulted in positive flow cytometric and complement-dependent cytotoxicity crossmatch. The splenic allograft was removed before intestinal transplantation and evaluated by H&E and immunohistochemical stains.ResultsExplanted donor splenic allograft showed several histopathologic changes: expanded red pulp secondary to congestion and marked neutrophilic and macrophage infiltration in the sinusoids, numerous neutrophilic microabscesses, and focal capillaritis. The C4d and IgG immunohistochemical stains were diffusely positive in the endothelial lining of the capillaries and sinusoidal lining, indicating diffuse IgG deposition and complement activation.ConclusionsWe propose that the noted changes are features of splenic acute antibody-mediated rejection (AMR). Additional cases are required to determine all the features of splenic AMR. To our knowledge, this is the first report of histopathologic changes in donor spleen after exposure to DSA for a short duration.

Chronic Liver Diseases (CLD) are characterized by abnormal accumulation of collagen fibrils, neo-angiogenesis, and sinusoidal remodeling. Collagen deposition along with intrahepatic angiogenesis and sinusoidal remodeling alters sinusoid structure resulting in portal hypertension, liver failure, and other complications. Efforts were made to develop treatments for CLDs. However, the success of such treatments is limited and unpredictable. We report a strategy for CLD treatment by induction of integrin αvβ3 mediated cell apoptosis using a rationally designed protein (ProAgio). ProAgio is designed to target integrin αvβ3 at a novel site. Integrin αvβ3 is highly expressed in activated Hepatic Stellate Cells (HSC), angiogenic endothelium, and capillarized Liver Sinusoidal Endothelial Cells (LSEC). ProAgio induces apoptosis of these disease causative cells. Tests with liver fibrosis mouse models demonstrate that ProAgio reverses liver fibrosis and relieves blood flow resistance by depleting activated HSC and capillarized LSEC. Our studies demonstrate an effective approach for CLD treatment., As activated hepatic stellate cells and liver sinusoidal endothelial cells express high levels of integrin α v β3, Turaga et al. present a strategy for treatment of chronic liver disease using their rationally designed protein (ProAgio) which targets integrin α v β3. They find that ProAgio –mediated apoptosis of these disease-associated cells reverses liver fibrosis and ameliorates intrahepatic vascular resistance in a mouse model

Sinusoidal obstruction syndrome (SOS) is a unique form of liver injury that occurs after exposure to chemotherapeutic drugs and toxins. The diagnosis of SOS in humans remains a challenge as the clinical criteria have low specificity and there are no reliable noninvasive biomarkers. The mechanism of injury is believed to be damage to liver endothelial cells, primarily sinusoidal endothelial cells (SECs), which leads to sinusoidal dilation, central venous fibrosis, and/or nodular regeneration. Nonclinical data suggest that this uncommon liver toxicity can be recapitulated in cynomolgus monkeys, and it is critical that pathologists are familiar with its characteristic clinicopathologic features. Elevations in liver enzymes, in particular aspartate aminotransferase, associated with isolated thrombocytopenia, should raise the suspicion of SEC injury for specific drug classes. Characterization of liver microscopic findings in monkeys benefits from the use of appropriate stains, such as reticulin stain, and VEGFR2 and CD34 immunohistochemical (IHC) stains. CD41 IHC demonstrates platelet accumulation in injured sinusoids, the likely cause of thrombocytopenia commonly reported in SOS. In conclusion, this report provides a comprehensive characterization of the pathology findings of drug-induced SOS in monkeys with the objectives of ensuring appropriate nonclinical recognition of the liability and informing clinical development strategy and monitoring.

We used in our study Twenty rats ,divided into two groups .the first group consist of 10 rats considered as a control group, while the second group treated with 0.05 mlbody weightday of dipyron injected for 30 days duration. The toxic effect of dipyrone was obvious in the different tissue and haematotoxic effects . The histological changes were obvious in the hepatic cell whichof liver were characterized by atrophy ,irregular hepatic cells ,RBC cells in the blood sinusoid. However,the spleen tissue contains nodule (white pulpe ).The bony tissue have osteocytes large bony vacuoles and the blood vessel were congested.

A 78-year-old woman was referred to our hospital because of repetitive suppurative arthritis at the artificial left knee joint. Her plasma brain natriuretic peptide level was 122 pg/mL. A 12-lead electrocardiogram showed a QS pattern in the inferior leads. A two-dimensional echocardiogram revealed hypokinesis at the inferior wall and hypertrophy at the apical lateral wall. Color flow imaging revealed this hypertrophic region to be a myocardial sinusoid, demonstrating diastolic coronary to left ventricular flow and early systolic flow vice versa. This was a very rare case of coronary to left ventricular fistula through a sinusoid without cyanotic congenital heart disease or severe coronary artery disease.

Introduction: Plasmalemmal vesicle-associated protein (PLVAP) is an endothelial-specific integral membrane glycoprotein that localizes to caveolae and fenestrae in animal models; however, little is known about PLVAP in endothelial cells (ECs) in hepatic sinusoids during liver cirrhosis (LC). Here, we aimed to elucidate PLVAP localization and expression in the human liver during LC progression. Methods: PLVAP protein expression was detected in specimens from normal control livers and hepatitis C-related cirrhotic livers using immunohistochemistry, Western blotting, and immunoelectron microscopy. Results: PLVAP mainly localized to the peribiliary capillary plexus (PCP) and was rarely observed in hepatic artery branches and portal venules in control tissue, but was aberrantly expressed in capillarized sinusoids and proliferated capillaries in fibrotic septa within cirrhotic liver tissue. Ultrastructural analysis indicated that PLVAP localized to thin ECs in some caveolae, whereas PLVAP localized primarily to caveolae-like structures and proliferative sinusoid capillary EC vesicles in cirrhotic liver tissue. Western blot analysis confirmed that PLVAP was overexpressed at the protein level in advanced cirrhotic liver tissue. Conclusion: PLVAP was strongly expressed in the caveolae of proliferated capillaries directly connected with sinusoids linked with the PCP, suggesting that it plays a role in angiogenesis and sinusoidal remodeling in LC.

Microcystin-leucine arginine (MC-LR) has reproductive and developmental toxicities. Previous studies indicated that gestational exposure to MC-LR induced fetal growth restriction in mice. The aim of this study was to further evaluate the effect of paternal MC-LR exposure before mating on fetal development. Male mice were intraperitoneally injected with either normal saline or MC-LR (10 μg/kg) daily for 35 days. Male mouse was then mated with female mice with 1:1 ratio. There was no significant difference on the rates of mating and pregnancy between MC-LR-exposed male mice and controls. Body weight and crown-rump length were reduced in fetuses whose fathers were exposed to MC-LR. Despite no difference on relative thickness of labyrinthine layer, cell proliferation, as measured by Ki67 immunostaining, was reduced in labyrinth layer of MC-LR-exposed mice. Moreover, blood sinusoid area in labyrinth layer was decreased in the fetus whose father was exposed to MC-LR before mating. Correspondingly, cross-sectional area of CD34-positive blood vessel in labyrinth layer was lower in fetuses whose fathers were exposed to MC-LR than in controls. These results provide evidence that paternal MC-LR exposure before mating induces fetal growth restriction partially through inhibiting cell proliferation and vascular development in labyrinth layer.

Oxidative stress is a common cause of organ damage, including liver injury. The purpose of this study was to observe the hepato-protective effects of sea cucumber (Holothurian edulis spp.) on rats suffering from alloxan-induced liver injury. This was an experimental study using Wistar strain rats. The rats were randomly divided into six groups, each containing six rats (a control group, an alloxan-only group, a glibenclamide group, and ethanol extract of sea cucumber groups divided into three doses). After the rats were given alloxan, researchers intervened with ethanol extract of sea cucumber and glibenclamide for 12 days. At the end of the study, the rats were sacrificed and their liver histopathologies were determined. The results revealed sinusoid dilatation and congestion, central veins that were not intact, dilated portal veins and bile ducts in the portal area, and a histiocytic appearance of the cellular architecture in the alloxan group. However, in the ethanol extract of sea cucumber groups, the sinusoid began narrowing and the central venous was intact, especially in the 200 mg/200 gBW/day dose group. This study showed that ethanol extract of sea cucumber has potential as a hepato-protective agent that might be due to reduction of oxidative damage by decreased free radical generation.

Purpose Clinical use of perimetric testing in patients with glaucoma typically assumes that perimetric defects will be less deep for larger than smaller stimuli. However, studies have shown that very large sinusoidal stimuli can yield similar defects as small circular stimuli. In order to provide guidelines for new perimetric stimuli, we tested patients with glaucoma using five different stimuli and compared defects to their patterns of retinal nerve fibre layer (RNFL) damage. Methods Twenty subjects with glaucoma were imaged with optical coherence tomography (OCT) volume scans to allow for en face RNFL images and were also tested on a custom perimetry station with five stimuli: Goldmann sizes III and V, a two‐dimensional Gaussian blob (standard deviation 0.5°) and a 0.5 cycle degree−1 sinusoidal grating presented two ways: flickered at 5 Hz, and pulsed for 200 ms instead of flickered. En face RNFL images were reviewed with the visual field locations overlaid, and each location was labelled for a patient as either no visible RNFL defect or as wedge, slit, edge, or diffuse defect. Nineteen age‐similar controls were tested with the same stimuli to define depth of defect as difference from mean normal. Bland‐Altman analysis was used to test three predictions of neural modelling by making five comparisons. Results Bland‐Altman analysis confirmed the three predictions. The flickered sinusoid gave deeper defects in damaged areas than the pulsed sinusoid (r = 0.25, p

Nonalcoholic fatty liver disease (NAFLD) is a rapidly increasing chronic liver disorder worldwide accompanied by hepatic steatosis, inflammation, fibrosis, and severe liver failure. Unfortunately, an effective treatment strategy for NAFLD has not yet been established, which has been hampered by the limited understanding of the pathophysiological drivers for NAFLD. To examine the unknown cellular and molecular mechanisms in the pathogenesis of NAFLD, there is an increasing need for the direct in vivo observation of hepatic microenvironments over extended periods of time. In this work, using a custom-built intravital imaging system and a novel fluorescent lipid droplet labeling dye, Seoul-Fluor 44 (SF44), we established an intravital imaging method to visualize individual lipid droplets and microvasculature simultaneously in the liver of live mice in vivo. In addition, in the nonalcoholic steatosis and steatohepatitis mouse model induced by a methionine and choline-deficient diet, we longitudinally visualized and quantitatively analyzed the development of lipid droplets in hepatocytes and sinusoid at a subcellular resolution during the progression of NAFLD up to 21 days in vivo.

Visceral leishmaniasis (VL) is the most severe form of leishmaniasis caused by protozoan parasites of the genus Leishmania. Hepatomegaly is one of the most frequent clinical manifestations of VL, whereas immunopathology of the symptom has not been well investigated. Using our chronic model of experimental VL, we examined the influence of Leishmania donovani infection on the liver by clinical, histological, and biochemical analyses. The infected mice showed increased liver weight 24 weeks post-infection. Although an increase in serum ALT and inflammatory cell accumulation were observed in the livers of infected mice, no apparent parenchymal necrosis or fibrosis was observed. Tissue water content analyses demonstrated that increased liver weight was predominantly due to an increase in water weight. Together with the finding of hepatic sinusoidal dilation, these results suggested that edema associated with sinusoidal dilation causes hepatomegaly in L. donovani infection. Immunostaining of platelets and erythrocytes showed no thrombus formation or damage to the sinusoidal endothelium in the liver of infected mice. Taken together, these results suggest that hepatomegaly during experimental VL is caused by non-obstructive sinusoidal dilation.

// Long-Hai Feng 1, 2, 3, * , Han Wang 1, 2, 3, * , Hui Dong 1, 2, 3 , Yu-Yao Zhu 1, 2, 3 and Wen-Ming Cong 1, 2, 3 1 Department of Pathology, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Yangpu, Shanghai, 200438, China 2 Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (Second Military Medical University) Ministry of Education, Yangpu, Shanghai, 200438, China 3 Shanghai Key Laboratory of Hepatobiliary Tumor Biology (Eastern Hepatobiliary Surgery Hospital ), Yangpu, Shanghai, 200438, China * Authors contributed equally to this work and serve as co-first authors Correspondence to: Wen-Ming Cong, email: wmcong@smmu.edu.cn Keywords: HGDNs, WD-SHCCs, stromal changes, diagnosis, differential diagnosis Received: April 09, 2017 Accepted: August 17, 2017 Published: September 01, 2017 ABSTRACT Aim: The stromal invasion has been regarded as the most valuable clue to distinguish high-grade dysplastic nodules (HGDNs) and well-differentiated small hepatocellular carcinomas (WD-SHCCs). The purposes of this study are to explore the stromal morphological changes for the differential diagnosis of these two equivocal lesions. Results: Based on the systemic studies of histological characteristics of HGDNs and WD-SHCCs, the stromal morphological changes, including sinusoid capillarization, ductular reaction and solitary artery, were performed to make a differential diagnosis between them. Separately, the solitary artery had the best sensitivity (93.75%) and accuracy (88.89%), and the sinusoid capillarization had the best specificity of 90.32%. On the whole, when at least 2 stromal morphological changes were abnormal, no matter what combination, the diagnostic performance was favorable and optimal with the highest accuracy of 92.06%, balancing the sensitivity (93.75%) and specificity (90.32%). The diagnostic performances were prior to the classical immunohistochemical panel comprising heat shock protein 70, glypican 3 and glutamine synthetase with the best sensitivity, specificity and accuracy of 62.50%, 80.65% and 71.43%, respectively. Materials and Methods: A retrospective case-control study was conducted on 63 patients who underwent partial hepatectomy for uninodular HGDNs or WD-SHCCs at the Eastern Hepatobiliary Surgery Hospital from 2005 to 2015. Conclusions: The stromal morphological changes, containing sinusoid capillarization, ductular reaction and solitary artery could provide a more considerable diagnostic and differential diagnostic performance between HGDNs and WD-SHCCs. And they should be the key points during the histopathological diagnosis.

Background and Aim There still lacks a tool for precisely evaluating cirrhotic remodeling. Histologic distortion characterized in cirrhosis (i.e. cirrhotic patterns) has a validated pathophysiological meaning and the potential relevance to clinical complications. We aimed to establish a new tool for quantify the cirrhotic patterns and test it for reflecting the cirrhotic remodeling. Methods We designed a computerized algorithm (qCP) dedicated for the analysis of liver images acquired by second harmonic microscopy. We evaluated its measurement by using a cohort of 95 biopsies (Ishak staging F4/5/6 = 33/35/27) of chronic hepatitis B (CHB) and a carbon tetrachloride-intoxicated rat model for simulating the bidirectional cirrhotic change. Results QCP can characterize 14 histologic cirrhosis parameters (HCPs) involving the nodules, septa, sinusoid and vessels. For CHB biopsies, the mean overall intra- and inter-observer agreement was 0.94 ± 0.08 and 0.93 ± 0.09, respectively. The robustness in resisting sample adequacy-related scoring error was demonstrated. The proportionate areas of total (CPA), septal (SPA), sinusoidal, and vessel collagen, nodule area, and nodule density (ND) were associated with Ishak staging (p

Among the various consequence arising from lung injury, hepatic fibrosis is the most severe. Decreasing the effects of hepatic fibrosis remains one of the primary therapeutic challenges in hepatology. Dysfunction of hepatic sinusoidal endothelial cells is considered to be one of the initial events that occur in liver injury. Vascular endothelial growth factor signaling is involved in the progression of genotype changes. The aim of the present study was to determine the effect of the tyrosine kinase inhibitor, vatalanib, on hepatic fibrosis and hepatic sinusoidal capillarization in a carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis. Liver fibrosis was induced in BALB/c mice using CCl4 by intraperitoneal injection for 6 weeks. The four experimental groups included a control, and three experimental groups involving administration of CCl4, vatalanib and a combination of the two. Histopathological staining and measuring live hydroxyproline content evaluated the extent of liver fibrosis. The expression of α-smooth muscle actin (SMA) and cluster of differentiation (CD) 34 was detected by immunohistochemistry. Collagen type I, α-SMA, transforming growth factor (TGF)-β1 and vascular endothelial growth factor receptor (VEGFR) expression levels were measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The average number of fenestrae per hepatic sinusoid was determined using transmission electron microscopy. Liver fibrosis scores and hydroxyproline content were decreased in both vatalanib groups. In addition, both doses of vatalanib decreased mRNA expression levels of hepatic α-SMA, TGF-β1, collagen-1, VEGFR1, and VEGFR2. Levels of α-SMA and CD34 protein were decreased in the vatalanib group compared with the CCl4 group. There were significant differences in the number of fenestrae per sinusoid between the groups. The present study identified that administration of vatalanib was associated with decreased liver fibrosis and hepatic sinusoidal capillarization in CCl4-induced mouse models, and is a potential compound for counteracting liver fibrosis.

Human immunodeficiency virus and antiretroviral therapy (ART) together can be far more detrimental to liver cells than either of the two unaided. However, ultrastructural aspects of the synergistic effects of HIV and ART have been understudied. In a patient cohort receiving ART, this study characterizes ultrastructurally sinusoidal degeneration, hepatocytic aberrations, mitochondrial dysfunction, accumulation of bulky lipid droplets (steatosis), and occlusion of sinusoidal lumina. Mitochondrial dysfunction causes the accumulation of acetyl-CoA which leads to insulin upregulation and resistance, lipid synthesis, and steatosis. Lipid droplets deposited in the sinusoids could be the source of the blood's lipid profile alterations in HIV patients on ART.

The liver plays a complex role in metabolism and detoxification, and better tools are needed to understand its function and to develop liver-targeted therapies. In this study, we establish a mechanobiological model of liver transport and hepatocyte biology to elucidate the metabolism of urea and albumin, the production/detoxification of ammonia, and consumption of oxygen and nutrients. Since hepatocellular shear stress (SS) can influence the enzymatic activities of liver, the effect of SS on the urea and albumin synthesis are empirically modeled through the mechanotransduction mechanisms. The results demonstrate that the rheology and dynamics of the sinusoid flow can significantly affect liver metabolism. We show that perfusate rheology and blood hematocrit can affect urea and albumin production by changing hepatocyte mechanosensitive metabolism. The model can also simulate enzymatic diseases of the liver such as hyperammonemia I, hyperammonemia II, hyperarginemia, citrollinemia, and argininosuccinicaciduria, which disrupt the urea metabolism and ammonia detoxification. The model is also able to predict how aggregate cultures of hepatocytes differ from single cell cultures. We conclude that in vitro perfusable devices for the study of liver metabolism or personalized medicine should be designed with similar morphology and fluid dynamics as patient liver tissue. This robust model can be adapted to any type of hepatocyte culture to determine how hepatocyte viability, functionality, and metabolism are influenced by liver pathologies and environmental conditions.

Cavernous malformations, or cavernomas, of the CNS are rare neurovascular lesions. They are usually detected between the second and fifth decade of life. Cavernomas occur in both sporadic and familial forms. The latter are more frequent in Hispanic-Americans, accounting for up to 50% of cavernomas. In contrast, among Caucasians, the familial forms are encountered in only 10–20% of patients. Patients with familial forms are typically affected by multiple cavernomas, whereas sporadic forms mostly present with a single lesion. Natural history of the disease is predetermined by cavernoma genetics, ultrastructural features, location along the neural axis and hemodynamic alteration in the lesion and surrounding brain. In hereditary cases, cavernomas are characterized by an autosomal-dominant pattern of inheritance with incomplete penetrance. Three genes, namely CCM1, CCM2 and CCM3, responsible for development of the cavernomas have been identified to date (Akers et al., Neurosurgery 80(5):665–680, 2017). When their mutations express, loss of respective proteins leads to formation of the lesion, with dilated thin-walled sinusoids or caverns covered by a single layer of endothelium that has undeveloped interstitial junctions and subendothelial interstitium. Blood flow inside the sinusoids is low, predisposing to intraluminal stasis and thrombosis. Due to fragility of the sinusoid wall, a cavernoma causes repetitive microhemorrhages into the surrounding neural tissue with formation of perifocal hemosiderosis and reactive gliosis. Such local homeostatic instability produced by either genetic or reactive environmental factors (inflammation, breakdown of the blood-brain barrier, gliosis) may provoke intensive neoangiogenesis and proliferation of the sinusoids. Subsequently, lesions enlarge and grow, which may coexist with clinical progression.

Breast cancer screening is beneficial when it averts progression of disease to metastasis, but adverse effects to patients and unnecessary medical expense may result downstream from false positives. Achieving early breast cancer detection with high sensitivity and specificity remains a challenge that may be met by using acoustic radiation force to assess the mechanical properties of tissue. The objective of this study is to evaluate in vivo the diagnostic relevance of Viscoelastic Response (VisR)-derived metrics for mechanical anisotropy. We compare our in vivo human results against biopsy findings. This study analyzed 9 breast lesions (4 malignant, 5 benign) imaged in vivo in women with BIRADS-4 or -5 ratings after standard screening. VisR relative elasticity (RE), relative viscosity (RV), and peak displacement (PD) were measured for each transducer orientation, and fit to a sinusoid by least-squares minimization, extrapolating to 360°. The fits were phase-aligned, and the point-wise differences in each parameter between lesion and background were integrated over angle. Finally, the ratio of the maximum to the minimum parameter value was calculated to reflect the degree of anisotropy (DoA). DoAs by PD, RE, and RV were statistically significantly greater in background than in lesion for all malignant cases but statistically significantly smaller in background than in lesion for all benign cases (Wilcoxon, p < 0.05). Additionally, differences between lesion and background integrated over angle by RE, RV and PD were statistically significantly different (Wilcoxon, p < 0.05) for malignant and benign lesions across all examined patients. These results suggest that VisR-derived mechanical anisotropy assessment could be diagnostically relevant for discriminating malignant from benign breast lesions.

Цель исследования иммуногистохимическая характеристика пелиоза печени. Методика. Образцы опухолей печени (n4) изучали с использованием гистологического, гистохимического (импрегнация AgNO3) и иммуногистохимического методов. В качестве первичных антител использовали антитела к Collagen III, Collagen IV, SMA, Ki67, CD31, CD34, catenin, CD10 и pCEA (Novocastra, UK). Вторичные антитела универсальные (HiDef Detectionтм HRP Polymer system, Cell Marque , США). Интенсивность иммуногистохимической окраски оценивали в баллах: 1 1(10 клеток), 2 (1150 клеток), 3 (51 клеток). Результаты представляли в процентах от общего числа иммунопозитивных клеток. Результаты. Гистологическое исследование показало, что стенка кисты представлена склерозированной волокнистой тканью с выраженной мононуклеарной инфильтрацией. В перипортальных трактах отчетливо выражены скопления гемосидерина и обширные зоны ступенчатого некроза. В прилежащей печеночной паренхиме определялись мультифокальные, синусоидальные эктазии с кровяным и/или плазменным содержимым, охватывающие все 3 зоны печеночной дольки. При гистохимическом исследовании в этих образованиях выявлялись ретикулярные волокна без признаков деструкции. При иммунногистохимическом исследовании вдоль синусоидов и выстилки полостей было обнаружено увеличение экспрессии Collagen III, Collagen IV (96.60.2 и 97.20.3 соответственно) и SMA (940,5). Степень экспрессии на CD31 (87.30.6) и CD34 (86.30.2) в эндотелии уменьшалась в направлении от триад к центральной вене. Индекс экспрессии Ki67 был увеличен в макрофагах (28.30.2) и лимфоцитах (12.30.7) синусоидов. Иммунонегативные реакции на catenin, CD10 и pCEA исключали опухолевый рост при пелиозе печени. Заключение. Активный синтез белков экстрацеллюлярного матрикса и пролиферация иммунокомпетентных клеток являются ключевыми процессами в патогенезе пелиоза печени на фоне разрушения эндотелиальных коммуникаций. Использованные методы могут быть полезны в дифференциальной диагностике пелиоза и опухолевых процессов в печени., Aim. Characterization of peliosis hepatis using immunohistochemical methods. Methods. The study was performed on archive autopsy samples from patients (n4) with peliosis hepatis using histological, histochemical (AgNO3 impregnation), and immunohistochemical methods. Murine monoclonal antibodies, anticollagen type III, anticollagen type IV, antismooth muscle actin, antiCD31, antiCD34, and antiKi67 (Novocastra, UK), were used as primary antibodies, and allpurpose antibodies (HiDef Detection HRP Polymer system, Cell Marque:, USA) were used as secondary antibodies. Intensity of immunohistochemical staining was expressed as scores: 1 110 of cells, 2 1150 of cells, and 3 51 of cells. Results. The cyst wall consisted of sclerotic fibrous tissue with pronounced mononuclear infiltration, accumulation of hemosiderin in periportal tracts, and zones of piecemeal necrosis. Multifocal, sinusoidal ectasias filled with blood and/or plasma components encompassing all three zones of the hepatic lobe were observed in the adjacent hepatic parenchyma. Histochemical study revealed reticular fibers without signs of destruction in these formations. Immunohistochemical analysis found increased expression of collagen III (96.60.2), collagen IV (97.20.3), and SMA (940.5) along sinusoids and cavity lining. The endothelial expression of CD31 (87.30.6) and CD34 (86.30.2) decreased on going from the hepatic triad to the central vein. The expression index, Ki67, was increased in sinusoid macrophages (28.30.2) and lymphocytes (12.30.7). Reactions to catenin, CD10 and pCEA were immunenegative, which excluded tumor growth. Conclusion. The study suggested that the active synthesis of extracellular matrix proteins and the immune cell proliferation are key processes in the pathogenesis of peliosis hepatis during destruction of endothelial communications in hepatic lobes., №2 (2019)

The liver and its zonation contribute to whole body homeostasis. Acute and chronic, not always liver, diseases impair proper metabolic zonation. Various underlying pathways, such as β-catenin, hedgehog signaling, and the Hippo pathway, along with the physiologically occurring oxygen gradient, appear to be contributors. Interestingly, hypoxia and hypoxia-inducible transcription factors can orchestrate those pathways. In the current review, we connect novel findings of liver zonation in health and disease and provide a view about the dynamic interplay between these different pathways and cell-types to drive liver zonation and systemic homeostasis.

Introduction Placental examination is recommended when genetic mutations cause fetal lethality in mice. But how fetal death alters histomorphology of the surviving mouse placenta is not known. Methods Placentas were examined at E17.5 after fetectomy of 1–2 fetal mice per pregnancy at either embryonic day (E) 15.5 (N = 8; Fx-2 group) or E13.5 (N = 5; Fx-4 group), which left 12 ± 2 surviving fetuses per litter. Results Fetectomy caused no changes in placental weights and no increases in placental hypoxia (pimonidazole staining). The size and cell morphology of the decidua and junctional zone regions were unchanged and, in the Fx-2 group, these regions became significantly less hypoxic. Significant changes in labyrinth volume included a 30% increase in the Fx-2 group and in both groups, a >50% decrease in % fetal blood space and >40% increase in % labyrinth tissue. Maternal blood sinusoid volume was unchanged. Cell death in the labyrinth was significantly increased (22-fold increase in TUNEL staining) whereas placental mRNA expression of the proliferation marker Mki67 was unchanged. mRNA expression of sFlt1 and Prl3b1 (mPL-II) was unchanged in the labyrinth and junctional zone tissues in the Fx-2 group and in whole placental tissue in the Fx-4 group. Discussion Placental examination of the junctional zone and decidual regions after spontaneous fetal death in late gestation is likely to yield useful phenotypic information and abnormalities that may contribute to fetal death. In contrast, labyrinth abnormalities including increased tissue volume and reduced fetoplacental vascularity may not be due to genetic perturbation nor predate fetal death.

This study reports the incidence of histological alterations in morphometric changes in the liver and ovary of Acanthopagrus latus collected from an urban stream impaired by anthropogenic activities and from a clean site (reference). Mercury concentration was determined using a standard cold vapor atomic absorption. The results showed that mercury concentration at the creek waters, and specially sediments along Mahshahr coast, was higher than in the other marine environment, and in Zangi was lower than in the other sites of sampling. Several liver lesions were identified, including enlarged and lateral nuclei, nuclear degeneration and vacuolation, oncotic, apoptic, focal, massive, centrilobular and periportal necrosis, atrophy, lipidosis, hydropic and cloudy swelling, oval cell proliferation, cirrhosis, hemorrhage, macrophage aggregates, bile stagnation, dilation of sinusoid, intracellular edema, and dark granules. Ovary histology revealed some changes in higher concentrations such as increase in the number of pre-vitellogenic oocytes, oocyte atresia, and adhesion in the ovaries of females that were sampled from the sites with high concentration of mercury. In this study, existence of mercury in Mahshahr coast is demonstrated and high incidence of histological alterations in the liver and ovary of A. latus is an evidence of the poor environmental quality of creek waters. Hence, histopathological changes were induced by the mercury adversely affected the proper functioning of these organs in these fish.

The liver is a center of metabolic activity, including the metabolism of drugs, and consequently is prone to drug-induced liver injury. Failure to detect hepatotoxicity of drugs during their development will lead to the withdrawal of the drugs during clinical trials. To avoid such clinical and economic consequences, in vitro liver models that can precisely predict the toxicity of a drug during the pre-clinical phase is necessary. This review describes the different technologies that are used to develop in vitro liver models and the different approaches aimed at mimicking different functional aspects of the liver at the fundamental level. This involves mimicking of the functional and structural units like the sinusoid, the bile canalicular system, and the acinus.

Portal vein thrombosis is considered to develop from portal venous vascular wall disorder, abnormal portal venous flow, and abnormalities of the blood coagulation system as the thrombogenic origins. Portal vein thrombosis can easily occur in patients with hepatic cirrhosis due to three additional factors. The first factor is the hyperpermeability of the gastrointestinal mucous membrane. Cirrhosis creates an environment susceptible to bacterial translocation, and loads to the flow of lipopolysaccharide into a portal vein, resulting in sinusoid wall injury. The second factor is clot formation promoted by portal venous congestion (sluggish blood flow) due to portal hypertension. The third factor is a decrease of antithrombin-III synthesis in liver cirrhosis. Among the underlying diseases of 539 cases of portal vein thrombosis in Japan in 2014, there were 434 cases (80.5%) of portal hypertension, whose breakdown consisted of 406 cases (75.3%) of liver cirrhosis, 25 cases of idiopathic portal hypertension, 8 cases of extrahepatic obstruction, and 7 cases of others, while 105 cases (19.5%) were not associated with portal hypertension. Secondary portal vein thrombus accounted for 69 (12.8%) of the total, if it is defined as that developed within 30 days after an operation or interventional radiology.

The study was carried out to investigate the effect of Shea oil on the histology and enzymes of liver of Albino Wistar rats. Twenty-five adult Albino Wistar rats weighing between 98.8g to 348g were randomly grouped into five groups of five rats each. Group I served as control and was given water and feed only ad libitum. Groups II, III, IV, and V were given 500 mg/kg, 1000 mg/kg, 1500 mg/kg, and 1500 mg/kg of Shea oil orally for the duration of 28days. Groups I-IV were sacrificed after 28days while Group V was left for additional 14 days post treatment after the rats in the group were sacrificed. Liver tissues were harvested for histopathological observations and blood samples were collected for liver function tests (Asparate aminotransferase (ASAT), Alanine aminotransferase (ALAT) and Alkaline phosphate (ALP)). Cell morphological changes seen under light microscopic level the rats in the control group have normal liver architecture while steatosis, fatty changes, inflammation, and necrosis where observed in the experimental groups. The hepatocytes were becoming irregular with narrowing sinusoid showing sign of recovery in group V. There was no significant effect on serum level of ASAT, ALP, total protein and urea while the change in ALAT and albumin level was significante (p>0.05). We therefore recommended that people consuming Shea oil should do so with care. Further investigations should be carried out.Keywords: Vitellaria Paradoxa, Enzymes and Liver

Hepatic sinusoidal dilatation refers to the enlargement of the hepatic capillaries. Most of the time this condition is caused by hepatic venous outflow obstruction, which results in vascular stasis and congestion of hepatic parenchyma. In this setting, hepatic sinusoidal dilatation can be related to pericardial disease, heart failure, compression or thrombosis of the hepatic veins or inferior vena cava (i.e., Budd-Chiari syndrome) or central veins/sinusoids involvement (i.e., sinusoidal obstruction syndrome). Nevertheless, some extrahepatic inflammatory conditions (such as pyelonephritis, cholecystitis, pneumonia, pancreatitis, intestinal bowel disease, and others) may be associated with hepatic sinusoidal dilatation without concurrent venous outflow obstruction. On contrast-enhanced cross-sectional imaging, hepatic sinusoidal dilatation is typically characterized by a mottled, reticular enhancement of the liver, usually referred to as "mosaic" pattern. Other hepatic and extrahepatic imaging features, such us the dilatation of the hepatic veins or the presence of ascites, can help in identifying the cause of sinusoidal dilatation.

The aim of the present study was to detect the effect of the recombinant human endostatin Endostar on hepatic sinusoidal capillarization in CCl4‑induced murine models of liver fibrosis. The liver fibrosis model was induced in BALB/c mice using intraperitoneal injection of CCl4 for 6 weeks. Animals were divided into the following six treatment groups: Group 1, normal animals; group 2, CCl4‑induced liver fibrosis; group 3, CCl4+Endostar 20 mg/kg/day for 6 weeks; group 4, CCl4+Endostar 10 mg/kg/day for 6 weeks; group 5, CCl4+Endostar 20 mg/kg/day for 4 weeks; and group 6, CCl4+Endostar 10 mg/kg/day for 4 weeks. The average number of fenestrae per hepatic sinusoid was determined using transmission electron microscopy. Vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) 1 and 2 expression was detected by western blot analysis. There were significant differences in the number of fenestrae per sinusoid between the normal control and untreated model fibrotic mice (P

Sinusoidal obstruction syndrome (SOS), previously known as veno-occlusive disease, is relatively rare subsequent to liver transplantation (LT). SOS refractory to medical therapy, however, can result in centrilobular fibrosis, portal hypertension and liver failure. Although sinusoidal endothelial cell damage around central venules (zone 3) occurs early in the development of SOS, the detailed mechanism of SOS development and its association with thrombocytopenia are not yet completely understood. The present report describes a patient who experienced SOS with unexplained thrombocytopenia following living donor LT. The progression of SOS resulted in graft dysfunction and the patient succumbed. The presence of platelets in the liver allograft was assayed immunohistochemically using antibody to the platelet marker cluster of differentiation 42b (platelet glycoprotein Ib). Platelet aggregates were found attached to hepatocytes along the sinusoid and within the cytoplasm of hepatocytes, particularly in zone 3. By contrast, no staining was observed in zone 1. These findings suggested that extravasated platelet aggregation in the space of Disse and the phagocytosis of platelets by hepatocytes were initiated by sinusoidal endothelial cell damage due to the toxicity of the immunosuppressant tacrolimus or a corticosteroid pulse, and that platelet activation and degranulation may be at least partially involved in the mechanism responsible for SOS.

Hepatic sinusoidal obstruction syndrome (SOS), a serious complication that mainly occurs after hematopoietic-stem cell transplantation (HSCT), is caused by damage to the sinusoidal endothelial cells after the obstruction of the sinusoid. Recently, hepatic SOS was reported to occur after non-HSCT chemotherapies. This report describes a patient who experienced hepatic SOS after non-HSCT chemotherapy for non-Hodgkin lymphoma. A liver biopsy showed the slight dilatation of the hepatic sinusoid, which may be indicative of hepatic SOS. Hepatic SOS should be included in the differential diagnosis of patients with severe liver injury following the administration of chemotherapy regimens that are toxic to the vascular endothelial cells.

SummaryChronic liver disease is associated with remarkable alterations in the intra- and extrahepatic vasculature. Because of these changes, the fields of liver vasculature and portal hypertension have recently become closely integrated within the broader vascular biology discipline. As developments in vascular biology have evolved, a deeper understanding of vascular processes has led to a better understanding of the mechanisms of the dynamic vascular changes associated with portal hypertension and chronic liver disease. In this context, hepatic vascular cells, such as sinusoidal endothelial cells and pericyte-like hepatic stellate cells, are closely associated with one another, where they have paracrine and autocrine effects on each other and themselves. These cells play important roles in the pathogenesis of liver fibrosis/cirrhosis and portal hypertension. Further, a variety of signaling pathways have recently come to light. These include growth factor pathways involving cytokines such as transforming growth factor β, platelet derived growth factor, and others as well as a variety of vasoactive peptides and other molecules. An early and consistent feature of liver injury is the development of an increase in intra-hepatic resistance; this is associated with changes in hepatic vascular cells and their signaling pathway that cause portal hypertension. A critical concept is that this process aggregates signals to the extrahepatic circulation, causing derangement in this system’s cells and signaling pathways, which ultimately leads to the collateral vessel formation and arterial vasodilation in the splanchnic and systemic circulation, which by virtue of the hydraulic derivation of Ohm’s law (pressure=resistance×flow), worsens portal hypertension. This review provides a detailed review of the current status and future direction of the basic biology of portal hypertension with a focus on the physiology, pathophysiology, and signaling of cells within the liver, as well as those in the mesenteric vascular circulation. Translational implications of recent research and the future directions that it points to are also highlighted.

Intratumor hemorrhage is a poor prognostic factor in pineal choriocarcinoma (PCCC). The aim of this study was to understand the relationship of tumor cells to the blood vessels to gain insights into the formation of intratumor hemorrhage in PCCC. The clinical data indicated that total tumor removal by surgical procedures followed immediately by radiotherapy and chemotherapy improved the prognosis in PCCC. The PCCC tissues removed from the patients were examined by histology and immunohistochemistry. Hematoxylin and eosin staining showed that the tumor stroma mainly consists of hemorrhagic tissues with tumor cells scattered inside. The pattern of distribution suggests that the tumor cells were possibly flushed and compressed by the bleeding. The tumor cells tended to form sinusoids that lacked CD34, but laminin expression provided evidence of vasculogenic mimicry. Interestingly, CD34-positive blood vessels were found connected to these sinusoids, suggesting that blood may flow from the tumor vasculature to the sinusoids. This may subsequently cause the enlargement of the sinusoids, blood clotting, the widening of the blood lakes, and eventually extensive hemorrhagic necrosis. Our study identified the key features of the PCCC vasculature. The findings add to the previous understanding of the formation of vascular channels, blood lakes, and extensive hemorrhagic necrosis. The intimate connections between the tumor-formed sinusoids and the blood vessels might be a major cause of severe hemorrhage in PCCC. The new information may be useful for the development of treatment strategies for managing PCCC.

Thirty -two (32) wistar rats were divided into four groups of eight. Group one was given 5ml/kgbw of normal saline and it served as the control, while groups two to four were given 100, 200 and 500 mg/kgbw of methanol extract Securidacalongepedunculata for twenty-eight (28) days. All the rats were maintained ad libitum on chick's mash and water. Sacrifices were done on the 7 th , 14 th , 21 st and 28 th day for the haematology and the histological examination was after the 28 th day. The result showed a significant (p

Tephrosia cinerea has been associated with ascites and liver fibrosis in sheep in Brazil. The dried plant was fed ad libitum to three sheep for 55–80 days. Three additional sheep were used as controls. All the treated sheep presented with hypoalbuminemia and increased γ-glutamyltransferase and aspartate aminotransferase activities. Anorexia, apathy, rough coat, ascites, and emaciation were observed after 45–60 days of feeding with T. cinerea . At necropsy 55–80 days after feeding of the plant commenced, the treated sheep had ascites, hydrothorax and hydropericardium, and their livers were firm and whitish, with a nodular surface. Histologically, the main hepatic lesions were periacinar fibrosis associated with hemorrhages and necrosis. On electron microscopy, a severe swelling of sinusoidal endothelial cells, frequently obstructing the lumen of the sinusoid was observed. The space of Disse was compressed by the swollen endothelial cells and microvilli usually present on the surface of hepatocytes adjacent to the space of Disse were not apparent. Dense bundles of collagen fibers were present in the spaces of Disse and within the sinusoids between profiles of swollen endothelial cells. It is concluded that T. cinerea causes periacinar fibrosis, similar to poisoning by Galenia africana in sheep and goats and veno-occlusive disease in different species.

Ginger (Zingeber officinale) is a natural dietary component with antioxidant and antiinflammation. In the present study, the influence of ginger ethanol extract on liver and spleen of mice was investigated. The animals were divided in to four groups then treated with different concentrations of ginger extract (0, 50, 75, 100 mg/ kg) for 10 days, and then the animals scarified to evaluate histological change on liver and spleen. Results showed that liver section of mice treated with (50 mg/kg) of extract exhibited no clear pathological lesion with the presence of moderate of kuppfer cell. While the sectional liver treated with (75 mg/kg) of extract showed double nuclei and proliferation of cells. Aggregation of mononuclear cells mainly macrophage and lymphocyte in liver parenchyma was observed in liver section of mice treated with (100 mg/kg) of extract. Spleen section of mice treated with (50 mg/kg) of extract showed hyperplasia of red pulp with proliferation with mononuclear cell around sinusoid form cord like structure. While, the sectional spleen treated with (75 mg/kg) of extract showed moderate hyperplasia of white pulp. Moderate peri-arterial hyper plasma and aggregate of lymphocyte and mononuclear cells in red pulp was notes in spleen section of mice treated with (100mg/kg) of extract.

Hereditary spherocytosis (HS) and sickle cell disease (SCD) are associated with splenomegaly and spleen dysfunction in pediatric patients. Scant data exist on possible correlations between spleen morphology and function in HS and SCD. This study aimed to assess the histologic and morphometric features of HS and SCD spleens, to get possible correlations with disease pathophysiology. In a large series of spleens from SCD, HS, and control patients, the following parameters were considered: (i) macroscopic features, (ii) lymphoid follicle (LF) density, (iii) presence of perifollicular marginal zones, (iv) presence of Gamna-Gandy bodies, (v) density of CD8-positive sinusoids, (vi) density of CD34-positive microvessels, (vii) presence/distribution of fibrosis and smooth muscle actin (SMA)-positive myoid cells, and (viii) density of CD68-positive macrophages. SCD and HS spleens had similar macroscopic features. SCD spleens had lower LF density and fewer marginal zones than did HS spleens and controls. SCD also showed lower CD8-positive sinusoid density, increased CD34-positive microvessel density and SMA-positive myoid cells, and higher prevalence of fibrosis and Gamna-Gandy bodies. HS had lower LF and CD8-positive sinusoid density than did controls. No significant differences were noted in red pulp macrophages. By multivariate analysis, most HS spleens clustered with controls, whereas SCD grouped separately. A multiparametric score could predict the degree of spleen changes irrespective of the underlying disease. In conclusion, SCD spleens display greater histologic effacement than HS, and SCD-related changes suggest impaired function due to vascular damage. These observations may contribute to guide the clinical management of patients.

Background & Aims Activated hepatic stellate cells (HSCs) located in the Disse's space play a crucial role in liver fibrosis. HAb18G/CD147, a tumor-related glycoprotein, is highly expressed in hepatocellular carcinoma cells and fibroblasts. Whether HAb18G/CD147 plays an important role in the hepatic fibrogenesis is unknown. Methods Immunohistochemistry for HAb18G/CD147 and α-smooth muscle actin expression in diseased liver tissues was used for correlation analysis. The function of HAb18G/CD147 in fibrogenesis was evaluated with the human HSCs LX-2 cell line and carbon tetrachloride-induced mouse liver fibrosis model. The specific antibody HAb18 targeting HAb18G/CD147 was injected intravenously into the mouse to investigate whether HAb18G/CD147 could be a potential target for liver fibrosis treatment. Results HAb18G/CD147 is highly expressed on activated HSCs in the sinusoid. The positive rates of HAb18G/CD147 expression in human HBV-related liver cirrhosis, liver biopsy with HBV and liver adjacent to hemangioma were 95.6% (65/68), 14.8% (8/54) and 6.4% (8/125), respectively. HAb18G/CD147 expression was significantly correlated with the Child–Pugh grade (r=0.2848, p =0.0186) and with the expression of α-smooth muscle actin in HSCs (r=0.4434, p =0.0002) in liver cirrhosis. Transforming growth factor-β1 upregulated HAb18G/CD147 expression in LX-2 cells. Transfection of HAb18G/CD147 promoted the profibrogenic genes expression. In mouse liver fibrosis model, HAb18G/CD147 expression increased with the development of fibrogenesis and decreased during the liver fibrosis spontaneous recovery. The HAb18 targeting HAb18G/CD147 could attenuate liver fibrosis. Conclusions These data suggest that HAb18G/CD147 plays a role in HSC activation and is a potential therapeutic target in fibrosis/cirrhosis.

The aim of this research was to observe the effect of Glytan on rat liver fibrosis and to investigate the mechanism of portal hypertension (PHT). SD male rats with weight between 240 g and 260 g were randomly divided into a sham group, model group, propranolol group, and Glytan group, according to their weight. PHT and liver fibrosis were induced by common bile duct ligation. After 2 and 4 weeks, the hydroxyproline (Hyp) content of liver tissues was tested by spectrophotometer. The collagen formation was evaluated by Masson staining and ultrastructural changes were evaluated by transmission electron microscopy (TEM). The results showed that Glytan inhibited the Hyp production at 2 weeks and 4 weeks. Masson staining revealed the same results with Hyp. Glytan inhibited the pseudolobule formation. TEM showed swelling sinusoid endothelial cells (SEC), reduced fenestra between the SEC, widened Disse's space, and reduced hepatocyte microvilli in the model group rats. At 4 weeks, loss of the hepatocyte microvilli and the basement membrane were clearly seen. Glytan promoted degeneration of the matrix and restoration of the SEC at 2 weeks and 4 weeks. It was concluded that Glytan inhibited collagen formation and ameliorated sinusoidal capillarization. This is one of the mechanisms of Glytan used to decrease the portal venous pressure. The results provided precise and reliable proof to develop new treatments for PHT.

AIM Apelin (APLN), the endogenous ligand of angiotensin-like receptor 1 (APJ), is a peptide necessary for embryonic and tumor angiogenesis. Little is known about the localization and changes of APLN expression including the sinusoids in human cirrhotic liver, which might contribute to portal hypertension. This study was designed to elucidate the localization and change of APLN expression in human liver during the progression of cirrhosis. METHODS Twelve normal liver specimens, eight specimens of Child-Pugh grade A cirrhosis, and 10 specimens of Child-Pugh grade C cirrhosis were studied. APLN protein and gene expression was examined by immunohistochemistry, western blotting, immunoelectronic microscopy, and laser captured microdissection (LCM) followed by polymerase chain reaction (PCR) in sinusoid. RESULTS In control liver tissue, APLN was localized mainly on arterial endothelial cells and hepatic arterioles in the portal tract. In cirrhotic liver tissue, aberrant APLN expression was observed in periportal capillary endothelial cells corresponding to capillarized sinusoids, and in proliferated arterial capillaries in the fibrotic septa. Significant overexpression of APLN at protein level in cirrhotic liver was demonstrated by western blotting (P

OBJECTIVE: Hepatic sinusoidal obstruction syndrome (HSOS) induced by a Chinese medicinal herb Tusanqi is increasingly being reported in recent years. The aim of the study was to investigate the possibility of using blood pyrrole-protein adducts test as a confirmatory diagnostic method. METHODS: Patients with HSOS according to international diagnostic criteria associated with Tusanqi from January 2006 to August 2010 in Zhongshan Hospital Fudan University were included and clinical features were collected. Pyrrole-protein adducts in blood sample were determined with ultra performance liquid chromatography-mass spectrometry (UPLC-MS) while pyrrolizidine alkaloids (PAs) in available herbal preparations were analyzed by high performance liquid chromatography-ultraviolet (HPLC-UV). RESULTS: Five patients (age 41–72 years, median age 54 years, all women) were included. Ascites (5/5), jaundice (5/5) and hepatomegaly (4/5) were common manifestations. The imaging features were diffused, patchy hepatic enhancement, periportal edema and ascites. Pathology ascertained that blood flow was obstructive at the site of sinusoid. PAs (Seneionine and seneciphylline) were identified in all the three available herbal preparations ingested by the HSOS patients. Pyrrole-protein adducts were unequivocally found in all the five blood samples. Two patients recovered, two developed chronic illness and one died due to liver failure and hepatic encephalopathy. CONCLUSIONS: The detection of blood pyrrole-protein adducts using a UPLC-MS approach is a specific, reliable, unambiguous and confirmatory test for HSOS induced by PA, and should be used together with the conventional HSOS clinical diagnostic criteria for the definitive diagnosis of PA-induced HSOS.

Background and Aim: The relationship between neovasculature in hepatocellular carcinoma (HCC) and the prognosis of patients still remains controversial. The aim of the present study was to investigate the prognostic significance of morphologic features of the microvessels in patients with HCC after resection. Methods: The paraffin-embedding specimens of 98 consecutive HCC patients, who received primary resection between 2000 and 2002, were collected from our prospective established tumor bank. The intratumoral microvessels were evaluated by immunohistochemical staining for CD31 and CD34. The disease-free survival (DFS) and overall survival (OS) of patients were analyzed by Kaplan–Meier analysis and Cox proportional hazards regression model. Results: There are two distinct microvessel types: capillary-like and sinusoid-like were identified in tumor tissues. The patients could be divided into two groups according to their microvessel types. Both DFS and OS of capillary group patients (n = 65) were better than those of sinusoid group patients (n = 33). Multivariate analyses showed that the microvessel type was an independent risk factor for DFS (P = 0.016) and OS (P = 0.004) of this cohort. Capillary-like microvessels were more common in small HCC, and were significantly associated with higher microvessel density, while sinusoid-like microvessels were significantly correlated with lower microvessel density. Conclusions: The results of our study suggested that the microvessel type is an effective predictor of survival in patients with HCC after resection, which might serve as potential novel therapeutic targets for prevention of the recurrence of HCC after resection.

Blood platelets play key roles in hemostasis and thrombosis and are the second most abundant cell type in the circulation. Due to their short life span of only a few days, anuclear platelets are continuously replenished and thus provide a classic system to study hematopoiesis. In mammals, platelets are produced by megakaryocytes (MKs) that are predominantly residing in the bone marrow (BM). MKs originate from hematopoietic stem cells and are thought to migrate from an endosteal niche towards the vascular sinusoids during their maturation. Unfortunately, previous studies on megakaryopoiesis were often limited by 2D imaging and cutting artefacts when analyzing bone sections, potentially resulting in underestimation of MK-to-vessel contacts and MK volumes. We studied megakaryopoiesis by visualizing MKs in their 3D environment. To this end, murine bones were simultaneously stained for MKs and endothelial cells, fixed, chemically cleared and imaged by Light Sheet Fluorescence Microscopy (LSFM). Thus, we achieved 3D-reconstructions of the complete and intact bone with subcellular resolution. Through imaging of MKs in the intact BM, we show that MKs can be found within the entire BM, without a bias towards bone-distant regions. We developed and compared different image processing pipelines and simulation scenarios for precise identification of MKs in 3D light-sheet fluorescence microscopy of uncut murine bones. By combining in vivo two-photon microscopy and in situ LSFM with computational simulations, we reveal surprisingly slow MK migration, limited intervascular space, and a vessel-biased MK pool. To complement limited imaging approaches computational simulations represent an important, well-controllable tool. Typically, simulation studies use artificial meshes as templates to minimize the computational effort or due to the lack of experimental data. Unfortunately, such simplified artificial templates for MKs and the vasculature can bias simulations and lead to misinterpretations as we show here. Using the segmented cell and vessel objects of true 3D images can overcome those limitations providing a simulation framework that has the prerequisites to maximally reflect the physiological situation. Thus, imaging and simulations go hand in hand when the respective 3D cell and vessel objects perfectly serve as biological templates for advanced simulations. We demonstrate reliable whole-bone analysis in silico, and found that MKs influence neutrophil and HSC migration as biomechanical restrainers modulating cell mobility and extravasation. These data challenge the current thrombopoiesis model of MK migration and support a modified model, where MKs at sinusoids are replenished by sinusoidal precursors rather than cells from a distant periostic niche (1). Furthermore, we identify MKs as biomechanical restraints for bone marrow cell mobilization. As MKs themselves do not need to migrate to reach the vessel, therapies to increase MK numbers might be sufficient to raise platelet counts. (1) Stegner D, van Eeuwijk JMM, Angay O, Gorelashvili MG, Semeniak D, Pinnecker J, Schmithausen P, Meyer I, Friedrich M, Dütting S, Brede C, Beilhack A, Schulze H, Nieswandt B, Heinze KG. Thrombopoiesis is spatially regulated by the bone marrow vasculature, Nat Commun. 2017 8(1):127. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

LYVE-1, a specific marker of lymphatics, is expressed in hepatic sinusoidal endothelium. A previous study revealed that LYVE-1 expression in sinusoidal endothelium was reduced in cirrhosis. However, it is still obscure how LYVE-1 expression in sinusoidal endothelium was reduced during the disease progression. To elucidate whether there were relationships among LYVE-1 attenuation, sinusoidal capillarization, and disease progression, we performed immunohistochemical investigations based on frozen human livers. Frozen liver sections of chronic hepatitis (n = 8), cirrhosis (n = 13), and normal/control liver (n = 10) were examined by immunostaining for lymphatic endothelial markers (LYVE-1 and D2-40) and vascular endothelial markers (CD31 and von Willebrand factor). Computer-aided morphometry was applied to obtain objective data. The diseased liver tissues were also examined ultrastructurally. In controls, sinusoidal endothelium was positive for LYVE-1 and CD31, but negative for D2-40 and von Willebrand factor. In chronic hepatitis and cirrhosis, LYVE-1 expression in sinusoidal endothelium was attenuated, especially in areas adjacent to active inflammatory or fibrotic lesions, while von Willebrand factor was reciprocally expressed in sinusoidal endothelium. The morphometric analyses revealed that LYVE-1 positivity in sinusoidal endothelium was significantly (P

Examination of needle liver biopsy specimens from 46 patients with Hodgkin's disease revealed sinusoidal dilatation with a predominantly centrolobular and midlobular localisation in 23 cases (50%). It was present in 90% of patients with general symptoms and in only 20% of those without them (p less than 0.001), and it was unrelated to the staging, the existence of hepatic infiltration by the disease and the lymph node histology. The pathogenesis of the sinusoidal ectasia is not known, but it might be a consequence of an alteration of the sinusoidal barrier, since no abnormality of the hepatocytes or of the hepatic venules was detected at light microscopy. Sinusoidal dilatation may be considered as a further systemic manifestation of Hodgkin's disease.

The histopathological picture of rat liver was studied after repeated envenomation with hornet (Vespa orientalis) venom sac extract (VSE). Light microscopical and histochemical investigation showed foci of necrosis of the hepatocytes, a decrease in glycogen content and in succinic dehydrogenase activity, some fat infiltration and an increase in alkaline phosphatase activity. Electron microscopy showed a decrease in the number of mitochondria per cell as well as a decrease in their cristae, enlargement of bile canaliculi, and destruction of the endothelium of the sinusoids bringing the cytoplasm of the necrotic hepatocytes in contact with the lumen of the sinusoid. The rat liver is proposed as a model for the study of pathological effects of animal toxins.