Rifaximin Prevents Intestinal Barrier Dysfunction and Alleviates Liver Injury in MCT-induced HSOS Mice.

OBJECTIVE: Rifaximin is an effective component of treatment strategies for liver and intestinal diseases. However, the efficacy of rifaximin in hepatic sinusoidal obstruction syndrome (HSOS) has not been explored. The present study aimed to investigate the efficacy and mechanism of rifaximin in HSOS. METHODS: An HSOS model was established in mice through the administration of monocrotaline (MCT, 800 mg/kg), and part of the HSOS mice were intragastrically administered with rifaximin. Then, the efficacy of rifaximin in HSOS was evaluated based on the liver pathological findings, liver proinflammatory cytokines, and alanine aminotransferase and aspartate aminotransferase levels. The Ussing chamber was used to evaluate the intestinal permeability, and tight junction (TJ) proteins were measured by Western blotting and real-time polymerase chain reaction to evaluate the intestinal barrier integrity. Then, the serum proinflammatory cytokine levels were evaluated by enzyme-linked immunosorbent assay. Afterwards, an in vitro experiment was performed to determine the relationship between rifaximin and TJ proteins. RESULTS: Rifaximin effectively alleviated the MCT-induced HSOS liver injury, suppressed the expression of liver proinflammatory cytokines, and reduced the serum levels of tumor necrosis factor-alpha and interleukin-6. Furthermore, rifaximin reduced the intestinal permeability, improved the intestinal barrier integrity, and promoted the expression of TJ proteins. CONCLUSION: The results revealed that the intestinal barrier integrity was destroyed in MCT-induced HSOS. The significant alleviation of MCT-induced HSOS induced by rifaximin might be correlated to the repairment of intestinal barrier integrity via the regulation of the TJ protein expression.

Metabolic Toxification of 1,2-Unsaturated Pyrrolizidine Alkaloids Causes Human Hepatic Sinusoidal Obstruction Syndrome: The Update.

Saturated and unsaturated pyrrolizidine alkaloids (PAs) are present in more than 6000 plant species growing in countries all over the world. They have a typical heterocyclic structure in common, but differ in their potential toxicity, depending on the presence or absence of a double bond between C1 and C2. Fortunately, most plants contain saturated PAs without this double bond and are therefore not toxic for consumption by humans or animals. In a minority of plants, however, PAs with this double bond between C1 and C2 exhibit strong hepatotoxic, genotoxic, cytotoxic, neurotoxic, and tumorigenic potentials. If consumed in error and in large emouns, plants with 1,2-unsaturated PAs induce metabolic breaking-off of the double bonds of the unsaturated PAs, generating PA radicals that may trigger severe liver injury through a process involving microsomal P450 (CYP), with preference of its isoforms CYP 2A6, CYP 3A4, and CYP 3A5. This toxifying CYP-dependent conversion occurs primarily in the endoplasmic reticulum of the hepatocytes equivalent to the microsomal fraction. Toxified PAs injure the protein membranes of hepatocytes, and after passing their plasma membranes, more so the liver sinusoidal endothelial cells (LSECs), leading to life-threatening hepatic sinusoidal obstruction syndrome (HSOS). This injury is easily diagnosed by blood pyrrolizidine protein adducts, which are perfect diagnostic biomarkers, supporting causality evaluation using the updated RUCAM (Roussel Uclaf Causality Assessment Method). HSOS is clinically characterized by weight gain due to fluid accumulation (ascites, pleural effusion, and edema), and may lead to acute liver failure, liver transplantation, or death. In conclusion, plant-derived PAs with a double bond between C1 and C2 are potentially hepatotoxic after metabolic removal of the double bond, and may cause PA-HSOS with a potential lethal outcome, even if PA consumption is stopped.

miR-511-3p promotes hepatic sinusoidal obstruction syndrome by activating hedgehog pathway via targeting Ptch1.

As a major complication of hematopoietic stem cell transplantation, the incidence of hepatic sinusoidal obstruction syndrome (HSOS) is as high as 70%. Previous evidence has demonstrated that miR-511-3p was involved in HSOS, but the mechanism remains unclear. This study aims to examine the mechanism underlying miR-511-3p regulating HSOS. Monocrotaline (MCT) was used to create an HSOS rat model and to treat liver sinusoidal endothelial cells (LSECs). Hematoxylin & eosin (H&E) and Masson staining were used to detect pathological changes in liver tissue. The expression of miR-511-3p and Hedgehog pathway-related proteins was assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. The effect of miR-511-3p in regulating HSOS was investigated by 3-(4,5)-dimethylthiahiazo-2)-3,5-diphenytetrazoliumromide (MTT), enzyme-linked immunosorbent assay (ELISA) assay, and flow cytometry. Finally, the interaction between miR-511-3p and patched1 (Ptch1) was determined by luciferase reporter assay. The rats showed a typical HSOS phenotype, including LSEC damage, liver injury, and fibrosis after MCT administration. miR-511-3p was upregulated in hepatic tissue of rat HSOS model and MCT-induced LSECs. miR-511-3p directly targeted Ptch1 and suppressed Ptch1 expression to activate the Hedgehog signaling pathway. Depletion of miR-511-3p showed a protective effect against MCT-induced HSOS, as evidenced by decreased HSOS pathogenesis factors, matrix metalloproteinases-2 (MMP-2), matrix metalloproteinases-9 (MMP-9), tumor necrosis factor-α (TNF-α), and interleukin 1 ß (IL-1ß), and decreased LSEC apoptosis rates. Nevertheless, knockdown of Ptch1 reversed the protective effect of miR-511-3p depletion against MCT-induced LSEC injury and apoptosis. miR-511-3p aggravates HSOS by activating the Hedgehog signaling pathway through targeting Ptch1, and miR-511-3p may develop as the potential therapy for the treatment of HSOS.NEW & NOTEWORTHY miR-511-3p is upregulated in HSOS in vivo and in vitro models. miR-511-3p activates the Hedgehog pathway by directly targeting Ptch1. Knockdown of miR-511-3p shows a protective effect against LSEC injury and apoptosis via Hedgehog signaling pathway. Inhibition of Ptch1 reserves the effect of miR-511-3p knockdown on LSEC damage and apoptosis.

The protective effects of umbilical cord-derived endothelial colony forming cells on hepatic veno-occlusive disease.

Hepatic veno-occlusive disease (HVOD) characterized by endothelial cell dysfunction is one of the serious complications after hematopoietic stem-cell transplantation or chemotherapeutic drug application. The mortality of HVOD patients with multiorgan dysfunction is as high as 80%. The primary aim of this study was to evaluate whether the infusion of human umbilical cord-derived endothelial colony forming cells (hUC-ECFCs) could mitigate HVOD injury and investigate the underlying mechanism. We found that the expression of chemokine C-X-C chemokine ligand 12 (CXCL12) was markedly increased in the livers of HVOD mice. Meanwhile, hUC-ECFCs infusion could significantly ameliorate liver injury in HVOD mice, which was accompanied by hUC-ECFCs recruitment in the liver, reduced liver pathological alterations, and decreased serum alanine aminotransferase and aspartate aminotransferase activity. Besides, CXCL12-induced migration in hUC-ECFCs was partly impeded by chemokine receptor type 7 (CXCR7) silence or CXCR4 blockage. In conclusion, our results demonstrated that hUC-ECFCs could mitigate HVOD through homing to the injured liver via the CXCL12-CXCR4/CXCR7 signaling pathway.

Inhibitory Effects of Beraprost Sodium in Murine Hepatic Sinusoidal Obstruction Syndrome.

BACKGROUND/AIM: In this study, the liver sinusoidal endothelial cells (LSECs)-protective effects of beraprost sodium (BPS) were investigated using mice with monocrotaline (MCT)-induced sinusoidal obstruction syndrome (SOS). MATERIALS AND METHODS: The mice were divided into BPS, placebo and control groups. They were killed 48 h after MCT administration, and blood samples and liver tissues were evaluated. Immunostaining was performed using anti-SE-1 and anti-CD42b antibodies, whereas plasminogen activator inhibitor (PAI-1) and endothelial nitric oxide synthase (eNOS) levels were evaluated using western blot or real-time RT-PCR. RESULTS: On pathological examination, SOS-related findings were observed in zone 3 in the placebo group; however, these were significantly suppressed in the BPS group. SE-1 staining showed a consistent number of LSECs in the BPS group compared with that in the placebo group, while CD42b staining showed a significant decrease in the number of extravasated platelet aggregation (EPA) in the BPS group. PAI-1 expression was significantly lower in the BPS group than in the placebo group; however, eNOS expression was significantly higher in the BPS group than in the placebo group. CONCLUSION: Prophylactic administration of BPS is useful for suppressing the development of SOS through the protective effects of LSEC.

NRF2 activates growth factor genes and downstream AKT signaling to induce mouse and human hepatomegaly.

BACKGROUND & AIMS: Hepatomegaly can be triggered by insulin and insulin-unrelated etiologies. Insulin acts via AKT, but how other challenges cause hepatomegaly is unknown. METHODS: Since many hepatomegaly-inducing toxicants and stressors activate NRF2, we examined the effect of NRF2 activation on liver size and metabolism using a conditional allele encoding a constitutively active NRF2 variant to generate Nrf2Act-hep mice in which NRF2 is selectively activated in hepatocytes. We also used adenoviruses encoding variants of the autophagy adaptor p62/SQSTM1, which activates liver NRF2, as well as liver-specific ATG7-deficient mice (Atg7Δhep) and liver specimens from patients with hepatic sinusoidal obstruction syndrome (HSOS) and autoimmune hepatitis (AIH). RNA sequencing and cell signaling analyses were used to determine cellular consequences of NRF2 activation and diverse histological analyses were used to study effects of the different manipulations on liver and systemic pathophysiology. RESULTS: Hepatocyte-specific NRF2 activation, due to p62 accumulation or inhibition of KEAP1 binding, led to hepatomegaly associated with enhanced glycogenosis, steatosis and G2/M cell cycle arrest, fostering hyperplasia without cell division. Surprisingly, all manipulations that led to NRF2 activation also activated AKT, whose inhibition blocked NRF2-induced hepatomegaly and glycogenosis, but not NRF2-dependent antioxidant gene induction. AKT activation was linked to NRF2-mediated transcriptional induction of PDGF and EGF receptor ligands that signaled through their cognate receptors in an autocrine manner. Insulin and insulin-like growth factors were not involved. The NRF2-AKT signaling axis was also activated in human HSOS- and AIH-related hepatomegaly. CONCLUSIONS: NRF2, a transcription factor readily activated by xenobiotics, oxidative stress and autophagy disruptors, may be a common mediator of hepatomegaly; its effects on hepatic metabolism can be reversed by AKT/tyrosine kinase inhibitors. LAY SUMMARY: Hepatomegaly can be triggered by numerous etiological factors, including infections, liver cancer, metabolic disturbances, toxicant exposure, as well as alcohol abuse or drug-induced hepatitis. This study identified the oxidative stress response transcription factor NRF2 as a common mediator of hepatomegaly. NRF2 activation results in elevated expression of several growth factors. These growth factors are made by hepatocytes and activate their receptors in an autocrine fashion to stimulate the accumulation of glycogen and lipids that lead to hepatocyte and liver enlargement. The protein kinase AKT plays a key role in this process and its inhibition leads to reversal of hepatomegaly.

Liquiritigenin and liquiritin alleviated monocrotaline-induced hepatic sinusoidal obstruction syndrome via inhibiting HSP60-induced inflammatory injury.

Hepatic sinusoidal obstruction syndrome (HSOS) is a life-threatening liver disease caused by the damage to liver sinusoidal endothelial cells (LSECs). Liquiritigenin and liquiritin are two main compounds in Glycyrrhizae Radix et Rhizoma (Gan-cao). Our previous study has shown that both liquiritigenin and liquiritin alleviated monocrotaline (MCT)-induced HSOS in rats via inducing the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant signaling pathway. This study aims to further investigate whether inhibiting liver inflammatory injury also contributed to the liquiritigenin and liquiritin-provided alleviation on MCT-induced HSOS. The results of serum alanine/aspartate aminotransferases (ALT/AST) activities and total bilirubin (TBil) amount, liver histological evaluation, scanning electron microscope observation and hepatic metalloproteinase-9 (MMP9) expression showed that liquiritigenin and liquiritin both alleviated MCT-induced HSOS in rats. Liquiritigenin and liquiritin reduced the increased liver myeloperoxidase (MPO) activity, mRNA expression of pro-inflammatory factors, hepatic infiltration of immune cells, hepatic toll-like receptor 4 (TLR4) expression and nuclear factor κB (NFκB) nuclear accumulation induced by MCT in rats. Furthermore, liquiritigenin and liquiritin attenuated MCT-induced liver mitochondrial injury, increased the decreased Lon protein expression and reduced the release of heat shock protein 60 (HSP60). Moreover, liquiritigenin and liquiritin also reduced NFκB nuclear accumulation and decreased the elevated cellular mRNA expression of NFκB-downstream pro-inflammatory cytokines induced by HSP60 in macrophage RAW264.7 cells. In conclusion, our study revealed that both liquiritigenin and liquiritin alleviated MCT-induced HSOS by inhibiting hepatic inflammatory responses triggered by HSP60.

Soluble Thrombomodulin Attenuates Endothelial Cell Damage in Hepatic Sinusoidal Obstruction Syndrome.

BACKGROUND: Hepatic sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease, is a form of drug-induced liver injury, the initial morphological changes associated with which occur in liver sinusoidal endothelial cells (LSECs). Recombinant human soluble thrombomodulin (rTM) is reported to have anti-inflammatory and cytoprotective effects. Therefore, we investigated the ability of rTM to protect endothelial cells and enhance their functions in a monocrotaline (MCT)-induced model of SOS. MATERIALS AND METHODS: Human umbilical vein endothelial cells were assessed in vitro following administration of MCT (2-4 mM) with/without rTM (10-100 ng/ml) to investigate the effect of rTM on cell proliferation and apoptosis. In vivo experiments were performed with Crl:CD1 mice divided into three groups: rTM (rTM + MCT), placebo (control diluent + MCT), and control (control diluent only). LSECs [cluster of differentiation (CD) 31+CD34+ vascular endothelial growth factor receptor 3 (VEGFR3)+ cells] from these mice were identified using fluorescence-activated cell sorting and assessed by quantitative real-time polymerase chain reaction (qPCR). RESULTS: In vitro, caspase-3 and -7 activities were significantly lower and cell viability (as assessed by MTT assays) significantly higher in the rTM group than in the placebo group. Moreover, levels of p-AKT increased upon rTM administration. In vivo, damage to LSECs in zone 3 of the hepatic acinus was attenuated and the number of LSECs were maintained in the rTM group, in contrast to the placebo group. Furthermore, expression of Nos3 (encoding endothelial nitric oxide synthase) was higher and that of plasminogen activator inhibitor 1 (Pai1) lower in LSECs from mice in the rTM group than in those from the placebo group. CONCLUSION: rTM can attenuate SOS by protecting LSECs and enhancing their functions.

Evaluation of the therapeutic effects of rice husk nanosilica combined with platelet-derived growth factor in hepatic veno-occlusive disease.

Veno-occlusive disease is an important pattern of hepatotoxicity associated with antineoplastic drugs. The study investigated the possible therapeutic effects of RHS nanoparticles combined with a PDGF on veno-occlusive disease (VOD) in liver elicited in rats with DAC. In this work, nanosilica (SiO2) was successfully prepared from rice husk, and its physicochemical characteristics were investigated using EDX, XRD, N2 adsorption-desorption isotherm, SEM, and TEM. Forty-eight male Sprague-Dawely rats were distributed into 6 groups, with 8 rats in each. The first group served as the control. In the second group, animals were infused with DAC (0.015 mg/kg; 1-3 days) by intraperitoneal injection (i.p.). In the third group, rats were injected i.p. with DAC, and then at 24 h following the last dose of DAC, received nano-RHS incorporated with PDGF twice a week for 4 weeks. In the fourth group, normal animals were injected with RHS. In the fifth group, normal rats received PDGF, and in the sixth group, normal rats received nano-RHS combined with PDGF. The prepared nanosilica showed type II adsorption isotherm characteristic for mesoporous materials with a specific surface area of 236 m2/g. TEM imaging confirmed the production of nanoparticles via the followed preparation procedure. Radical scavenging potential for nano-RHS was determined using two different in-vitro assays: DPPH, and ABTS radicals. The results of this work show that administration of nano-RHS combined with PDGF significantly reversed the oxidative stress effects of DAC as evidenced by a decrease in liver function. It can be concluded that the nano-RHS combined with PDGF is useful in preventing oxidative stress and hepatic VOD induced by chemotherapy such as DAC.

Venoocclusive disease due to chemotherapy for pediatric acute lymphoblastic leukemia is associated with increased levels of plasminogen-activator inhibitor-1.

We describe three cases of sinusoidal obstruction syndrome/venoocclusive disease (SOS) in pediatric patients with acute lymphoblastic leukemia (ALL). All three episodes occurred during or just after the induction or reinduction phase of treatment based on prednisone/dexamethasone, vincristine, daunorubicin, and pegylated-l-asparaginase. SOS episodes were categorized as mild/moderate and resolved in 7, 10, and 16 days using supportive measures or defibrotide therapy. In all three episodes, the clinical diagnosis of SOS was associated with a significant increase in plasminogen-activator inhibitor-1 (PAI-1) that reduced with patient clinical improvement. PAI-1 warrants study as a diagnostic marker for SOS in ALL.

Phosphodiesterase III inhibitor attenuates rat sinusoidal obstruction syndrome through inhibition of platelet aggregation in Disse's space.

BACKGROUND AND AIM: Sinusoidal obstruction syndrome (SOS) is a serious drug-induced liver injury. However, the pathophysiology of the disease remains unclear. This study investigated the effects of cilostazol (CZ), a phosphodiesterase III inhibitor, in a monocrotaline (MCT)-induced rat model of SOS. METHODS: Male Wistar rats were administrated MCT to induce SOS. Rats were divided into control, MCT, and MCT + CZ groups. In the MCT + CZ group, CZ was administered at 48 h, 24 h, and 30 min prior to and 8 h and 24 h after MCT administration. The MCT group was treated with water instead of CZ. At 48 h after MCT administration, blood and liver samples were collected to assess biochemistry and liver histology. Expression of rat endothelial cell antigen, CD34, CD41, P-selectin, and caspase-3 in the liver were analyzed. Plasminogen activator inhibitor-1 (PAI-1) in hepatocytes was analyzed using western blotting and polymerase chain reaction. RESULTS: In the MCT group, macroscopic findings showed a dark-red liver surface. Histological findings showed sinusoidal dilatation, coagulative necrosis of hepatocytes, and endothelial damage of the central vein. These changes were attenuated in the MCT + CZ group. Elevated serum transaminase and decreased platelet counts were observed in the MCT + CZ group compared with those in the MCT group. Treatment with CZ reduced MCT-induced damage to the liver sinusoidal endothelial cells, inhibited extravasated platelet aggregation, and suppressed hepatocyte apoptosis around the central vein. CZ attenuated hepatic PAI-1 protein and mRNA levels. CONCLUSIONS: Cilostazol attenuated MCT-induced SOS by preventing damage to liver sinusoidal endothelial cells and extravasated platelet aggregation. Hepatic PAI-1 levels were suppressed with CZ treatment.

Defibrotide: An Oligonucleotide for Sinusoidal Obstruction Syndrome.

OBJECTIVE: To review the efficacy and safety of defibrotide as well as its pharmacology, mechanism of action, pharmacokinetics (PK), drug-drug interactions, dosing, cost considerations, and place in therapy. DATA SOURCES: A PubMed search was performed through August 2017 using the terms defibrotide, oligonucleotide, hepatic veno-occlusive disease (VOD), sinusoidal obstruction syndrome (SOS), and hematopoietic cell transplantation (HCT). Other data sources were from references of identified studies, review articles, and conference abstracts plus manufacturer product labeling and website, the Food and Drug Administration website, and clinicaltrials.gov. STUDY SELECTION AND DATA EXTRACTION: English-language trials that examined defibrotide's pharmacodynamics, mechanism, PK, efficacy, safety, dosing, and cost-effectiveness were included. DATA SYNTHESIS: Trials have confirmed the safety and efficacy of defibrotide for treatment of VOD/SOS in adult and pediatric HCT patients, with complete response rates and day +100 overall survival rates ranging from 25.5% to 76% and 35% to 64%, respectively. The British Committee for Standards in Haematology/British Society for Blood and Marrow Transplantation Guidelines recommend defibrotide prophylaxis in pediatric and adult HCT patients with risk factors for VOD/SOS; however, its prophylactic use in the United States is controversial. Although there are efficacy data to support this strategy, cost-effectiveness data have not shown it to be cost-effective. Defibrotide has manageable toxicities, with low rates of grade 3 to 4 adverse effects. CONCLUSIONS: Defibrotide is the first medication approved in the United States for the treatment of adults and children with hepatic VOD/SOS, with renal or pulmonary dysfunction following HCT. Data evaluating defibrotide for VOD/SOS prevention are conflicting and have not shown cost-effectiveness.

Detection of Sp110 by Flow Cytometry and Application to Screening Patients for Veno-occlusive Disease with Immunodeficiency.

Mutations in Sp110 are the underlying cause of veno-occlusive disease with immunodeficiency (VODI), a combined immunodeficiency that is difficult to treat and often fatal. Because early treatment is critically important for patients with VODI, broadly usable diagnostic tools are needed to detect Sp110 protein deficiency. Several factors make establishing the diagnosis of VODI challenging: (1) Current screening strategies to identify severe combined immunodeficiency are based on measuring T cell receptor excision circles (TREC). This approach will fail to identify VODI patients because the disease is not associated with severe T cell lymphopenia at birth; (2) the SP110 gene contains 17 exons, making it a challenge for Sanger sequencing. The recently developed next-generation sequencing (NGS) platforms that can rapidly determine the sequence of all 17 exons are available in only a few laboratories; (3) there is no standard functional assay to test for the effects of novel mutations in Sp110; and (4) it has been difficult to use flow cytometry to identify patients who lack Sp110 because of the low level of Sp110 protein in peripheral blood lymphocytes. We report here a novel flow cytometric assay that is easily performed in diagnostic laboratories and might thus become a standard assay for the evaluation of patients who may have VODI. In addition, the assay will facilitate investigations directed at understanding the function of Sp110.

Extravasated platelet aggregation in the livers of rats with drug­induced hepatic sinusoidal obstruction syndrome.

Oxaliplatin-based chemotherapy plays an important role in the treatment of colorectal liver metastases. Oxaliplatin, however, causes sinusoidal obstruction syndrome (SOS), which is characterized by portal hypertension, splenomegaly, thrombocytopenia, and liver dysfunction. SOS is diagnosed histopathologically by disruption of the sinusoidal endothelium, collagen deposition, fibrosis especially around zone 3, dilatation of the sinusoidal space and congestion. This study assessed the characteristics of a rat model of SOS. SOS was induced in rats by administration of monocrotaline (MCT). Blood chemistries and macroscopic and microscopic findings were compared in rats administered MCT and vehicle (control group). Levels of expression in the liver of CD41, P­selectin, rat endothelial cell antigen­1, CD34, and cleaved caspase­3 were analyzed immunohistochemically. Moreover, livers of these rats were analyzed by electron microscopy. Macroscopically, MCT­treated rats showed accumulation of bloody ascites and blue liver and were diagnosed with SOS histologically. Serum concentrations of aspartate aminotransferase (P=0.003), alanine aminotransferase (P=0.008), total­bilirubin (P=0.012), direct­bilirubin (P=0.007), indirect­bilirubin (P=0.003), lactate dehydrogenase (P<0.001) and hyaluronic acid (P=0.016) were significantly higher, and platelet counts significantly lower (P=0.004), in MCT­treated than in control rats. The livers of MCT­treated rats were immunohistochemically positive for CD41 and P­selectin, suggesting platelet aggregates; for rat endothelial cell antigen­1 and CD34, suggesting sinusoidal endothelial disorder; and for cleaved caspase­3, suggesting hepatocyte apoptosis. Electron microscopic findings revealed platelet aggregation in the space of Disse in the MCT group. Extravasated platelet aggregation in Disse's space may be involved in the development of SOS.

Chemotherapy-induced Sinusoidal Injury (CSI) score: a novel histologic assessment of chemotherapy-related hepatic sinusoidal injury in patients with colorectal liver metastasis.

BACKGROUND: Preoperative neoadjuvant therapy for colorectal liver metastases (CRLM) is increasing in use and can lead to chemotherapy-induced damage to sinusoidal integrity, namely sinusoidal obstruction syndrome (SOS). SOS has been associated with an increased need for intraoperative blood transfusions, increased length of hospitalization post-surgery, decreased tumor response, and a shorter overall survival after resection due to liver insufficiency. It is critical for clinicians and pathologists to be aware of this type of liver injury, and for pathologists to include the status of the background, non-neoplastic liver parenchyma in their pathology reports. In this study, expression of CD34 by sinusoidal endothelial cells (SECs), increased expression of smooth muscle actin (SMA) by hepatic stellate cells (HSCs), and aberrant expression of glutamine synthetase (GS) by noncentrizonal hepatocytes were semiquantitatively evaluated in liver resection or biopsy specimens from patients with CRLM to determine their diagnostic value for assessing chemotherapy-induced sinusoidal injury (CSI). METHODS: The expression of each marker was compared among 22 patients with CRLM with histologically evident SOS (SOS+) and 8 patients with CRLM who had not undergone chemotherapy. Each case was given a histologic grade using the sinusoidal obstruction syndrome index score (SOS-I) to assess the likelihood of SOS. Cases were also given an immunohistochemical grade using the total CSI score calculated as the sum of CD34, SMA, and GS scores. RESULTS: Abnormal staining patterns for CD34 and SMA were significantly more frequent and extensive in SOS+ cases than in the controls (81.8% vs. 25%, P < 0.01; 72.7% vs. 25%, P = 0.03). Aberrant GS expression in midzonal and periportal hepatocytes was only observed in SOS+ cases (31.8% vs. 0%), but this difference did not reach statistical significance. The CSI score was significantly higher in the SOS+ cases when compared to controls (P < 0.01), and was associated with a higher SOS histologic grade (P = 0.02). CONCLUSIONS: The CSI score, calculated using an immunohistochemical panel consisting of CD34, SMA, and GS, may serve as an objective marker of chemotherapy-induced sinusoidal injury and could help diagnose this peculiar form of liver injury.

Quercetin and baicalein suppress monocrotaline-induced hepatic sinusoidal obstruction syndrome in rats.

Hepatic sinusoidal obstruction syndrome (SOS) is a rare liver disease with considerable mortality. This study is designed to observe the protection of quercetin and baicalein against monocrotaline (MCT)-induced SOS in rats and its engaged mechanism. Rats were pre-administrated with MCT (90mg/kg) to induce SOS, and 6, 30h later were orally given with quercetin and baicalein (40mg/kg) twice. Results of detecting rats with liver ascites, measuring serum transaminases, total bilirubin (TBil) and bile acids (TBA), analyzing blood cells, liver histological evaluation and scanning electron microscope observation all demonstrated the detoxification of quercetin and baicalein against MCT-induced SOS in rats. Quercetin and baicalein reduced the increased metalloproteinase-9 (MMP-9) expression, liver myeloperoxidase (MPO) activity, toll-like receptor (TLR)-2,3,6,9 expression and nuclear factor κB (NFκB) transcriptional activation induced by MCT. Quercetin and baicalein reduced MCT-induced nuclear translocation of early growth response1 (Egr1) and increased expression of Serpine1 and tissue factor (TF). Quercetin and baicalein reduced MCT-induced increased liver malondialdehyde (MDA) amount and enhanced the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). Quercetin and baicalein also abrogated MCT-induced activation of mitogen-activated protein kinases (MAPKs) and phosphatidylinositol 3-kinase (PI3K) signaling cascades. In conclusion, this study demonstrated the protection of quercetin and baicalein against MCT-induced SOS in rats, indicating the potential application of them for the treatment of SOS in clinic. Transcriptional factor NFκB, Egr1 and Nrf2-regulated inflammation, coagulation-fibrinolysis and antioxidant, and PI3K and MAPKs signaling cascades are all involved such protection.

The fifth epidermal growth factor-like region of thrombomodulin exerts cytoprotective function and prevents SOS in a murine model.

The present study found that the fifth epidermal growth factor-like domain of thrombomodulin (TME5) possesses the cytoprotective function in association with an increase in levels of anti-apoptotic myeloid cell leukemia-1 protein in an activated protein C-independent manner in human umbilical vein endothelial cells (HUVECs). Importantly, TME5 counteracted calcineurin inhibitor-induced vascular permeability and successfully prevented monocrotaline-induced sinusoidal obstruction syndrome (SOS) in a murine model. Taken together, TME5 may be useful for preventing or treating lethal complications that develop after hematopoietic stem cell transplantation such as SOS and thrombotic microangiopathy in which endothelial cell damage has a role.

Chlorogenic acid suppresses monocrotaline-induced sinusoidal obstruction syndrome: The potential contribution of NFκB, Egr1, Nrf2, MAPKs and PI3K signals.

Hepatic sinusoidal obstruction syndrome (SOS) is a highly lethal liver disease. This study aims to observe the protection and its engaged mechanism of chlorogenic acid (CGA) against monocrotaline (MCT)-induced SOS. Results of detecting liver ascites, measuring serum transaminases, liver histological evaluation and scanning electron microscope observation all demonstrated that CGA prevented MCT-induced SOS in rats. CGA reduced MCT-induced increased liver myeloperoxidase (MPO) activity, tumor necrosis factor (TNF)α and interleukin (IL)-1ß mRNA expression, toll-like receptor (TLR)-2,3,6,9 expression, and nuclear factor κB (NFκB) transcriptional activation. CGA also decreased MCT-induced early growth response1 (Egr1) activation. CGA reduced MCT-induced elevated liver malondialdehyde (MDA) amount and enhanced nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). CGA blocked MCT-induced PI3K and MAPKs activation. In conclusion, this study demonstrates the protection of CGA against MCT-induced SOS. Transcriptional factor NFκB, Egr1 and Nrf2-regulated inflammation, coagulation-fibrinolysis, and antioxidant, and PI3K and MAPKs all contribute to such protection.