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1.
Am J Pathol ; 190(3): 614-629, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31972159

RESUMO

Bacterial flagellin, recognized by cell surface of Toll-like receptor (TLR) 5, is a potent activator of many types of cells, leading to the activation of innate or adaptive immunity, which are pivotal in regulating fibrotic process. However, the exact role of TLR5 signaling in hepatic fibrogenesis remains unclear, and this study aims to elucidate its underlying mechanisms. Flagellin was injected to hepatotoxin- and cholestasis-induced liver fibrosis murine models. Flagellin-induced TLR5 activation significantly decreased the severity of liver fibrosis. Interestingly, the expression levels of IL-1 receptor antagonist (IL1RN) and interferon (IFN)ß markedly increased in fibrotic livers on flagellin treatment. Consistently, in vivo activation of TLR5 signaling markedly increased IFNß and IL1RN expression in the livers. Notably, flagellin injection significantly exacerbated the severity of liver fibrosis in IFN-α/ß receptor 1 (IFNAR1) knockout mice. Furthermore, hepatic expression of IL1RN in the fibrotic livers of IFNAR1 knockout mice was significantly lower than those of wild-type mice. In support of these findings, flagellin-mediated IL1RN production is not sufficient to alleviate the severity of hepatic fibroinflammatory responses in IFNAR1-deficient milieu. Finally, hepatic stellate cells treated with IL1RN had significantly decreased cellular activation and its associated fibrogenic responses. Collectively, manipulation of TLR5 signaling may be a promising therapeutic strategy for the treatment of liver fibrosis.


Assuntos
Colestase/complicações , Interferon beta/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Cirrose Hepática/fisiopatologia , Transdução de Sinais , Receptor 5 Toll-Like/metabolismo , Imunidade Adaptativa , Animais , Modelos Animais de Doenças , Progressão da Doença , Flagelina/administração & dosagem , Imunidade Inata , Interferon beta/genética , Proteína Antagonista do Receptor de Interleucina 1/genética , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/etiologia , Cirrose Hepática/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor de Interferon alfa e beta/genética , Receptor 5 Toll-Like/genética
2.
Life Sci ; 241: 117121, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31794772

RESUMO

AIMS: This study addressed whether endogenous hepatic stem/progenitor (HSP) cells survival were related to the injured signals during liver cirrhosis. MATERIAL AND METHODS: Liver cirrhosis was induced in C57BL/6 mice by administering diethylnitrosamine (DEN) in drinking water. Hematoxylin-eosin staining and Masson's trichrome staining were used to identify infiltrative cells and connective tissues, respectively. The inflammatory activity grade and fibrotic stage, represented as G and S respectively, and evaluated by the International Simplified Grading and Staging System (ISGSS). Endogenous HSP cells (Ng2+HSP) were identified by immunofluorescence staining with an anti-neuro/glial antigen 2 (Ng2) antibody. All data were analyzed using SPSS 22.0 and GraphPad Prism 6 and Student's t-test was performed to determine statistical significance. p-values < 0.05 were considered statistically significant. KEY FINDINGS: All mice administered oral DEN developed liver fibrosis, liver cirrhosis and hepatocellular carcinoma (HCC). During the fibrosis period, observed a positive correlation of survival of endogenous HSP (Ng2+HSP) cells with inflammatory activity. As the disease developed into the cirrhotic stage, when lost correlation of endogenous HSP cells with inflammatory activity, revealed a dramatically reduced survival rate of endogenous HSP (Ng2+HSP) cells. SIGNIFICANCE: The DEN-induced liver cirrhosis could develop into three time zone of fibrosis, cirrhosis and cancer, and the histological patterns in the model are similar to those described in humans. Dramatic survival and less apoptosis of endogenous HSP (Ng2+HSP) cells was within fibrotic state, where inflammation signals is strong, indicating such time zone (1-6 weeks) during liver cirrhosis is important for mobilizing endogenous HSP-based regeneration.


Assuntos
Carcinoma Hepatocelular/terapia , Inflamação/terapia , Cirrose Hepática/terapia , Neoplasias Hepáticas Experimentais/terapia , Fígado/citologia , Células-Tronco/citologia , Animais , Carcinoma Hepatocelular/etiologia , Dietilnitrosamina/toxicidade , Modelos Animais de Doenças , Inflamação/etiologia , Fígado/imunologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Neoplasias Hepáticas Experimentais/etiologia , Regeneração Hepática , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco/fisiologia
3.
Zhonghua Nei Ke Za Zhi ; 58(12): 894-898, 2019 Dec 01.
Artigo em Chinês | MEDLINE | ID: mdl-31775452

RESUMO

Objective: Portal vein thrombosis (PVT) is a rare and severe clinical manifestation of antiphospholipid syndrome (APS), as well as a predictor of poor prognosis. This study was conducted to explore the clinical features and risk factors of PVT in APS patients. Methods: A total of 123 APS patients diagnosed from 2012 to 2019 were retrospectively enrolled. The diagnosis of PVT was made according to the 2009 American College of Liver Diseases (AASLD) criteria. Clinical and laboratory data were collected. A multivariate (MV) logistic regression model was constructed using a stepwise forward selection procedure among those candidate univariables with P values<0.10. Results: A total of 28 cases with PVT, and 95 control cases without PVT were finally enrolled.The 28 APS-PVT patients included 5 males and 23 females with age range from 17 to 63 years. Clinical manifestations included acute thrombosis in 8 patients, chronic thrombosis in 16, and 4 with portal vein spongiform. As to the involved vessels, single portal vein thrombosis was seen in 20 patients, portal combined with superior mesenteric vein (SMV) and splenic vein in one patient, portal plus SMV in 4 and only SMV in 3 patients. Other manifestations were portal hypertension (16/28), esophageal varices (13/28), spleen infarction (7/28) and gastrointestinal bleeding (4/28). Two antiphospholipid antibodies were positive in 13 cases. Triple positive antibodies were seen in 7 cases. Multivariate logistic regression analysis showed that disease duration less than 0.5 years (OR=72.74, 95%CI 7.50-705.45, P<0.001), hypoalbuminemia (OR=356.45, 95%CI 19.19-6 620.14, P<0.001), and elevated erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP) (OR=14.41, 95%CI 1.49-139.20, P<0.001) were independent risk factors for PVT in APS. Conclusion: PVT is usually misdiagnosed due to insidious onset. Short disease duration, hypoalbuminemia and elevated ESR/CRP are risk factors for PVT in APS. Better understanding, early diagnosis and treatment will improve the clinical outcome.


Assuntos
Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/imunologia , Cirrose Hepática/imunologia , Veia Porta/patologia , Trombose/imunologia , Trombose Venosa/fisiopatologia , Adolescente , Adulto , Síndrome Antifosfolipídica/complicações , Feminino , Humanos , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Trombose/complicações , Trombose Venosa/complicações , Adulto Jovem
4.
Nat Med ; 25(10): 1560-1565, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31591593

RESUMO

Therapies to reduce liver fibrosis and stimulate organ regeneration are urgently needed. We conducted a first-in-human, phase 1 dose-escalation trial of autologous macrophage therapy in nine adults with cirrhosis and a Model for End-Stage Liver Disease (MELD) score of 10-16 (ISRCTN 10368050). Groups of three participants received a single peripheral infusion of 107, 108 or up to 109 cells. Leukapheresis and macrophage infusion were well tolerated with no transfusion reactions, dose-limiting toxicities or macrophage activation syndrome. All participants were alive and transplant-free at one year, with only one clinical event recorded, the occurrence of minimal ascites. The primary outcomes of safety and feasibility were met. This study informs and provides a rationale for efficacy studies in cirrhosis and other fibrotic diseases.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Doença Hepática Terminal/terapia , Cirrose Hepática/terapia , Macrófagos/transplante , Idoso , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Relação Dose-Resposta Imunológica , Doença Hepática Terminal/imunologia , Doença Hepática Terminal/patologia , Feminino , Humanos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Regeneração Hepática , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade
5.
Curr Med Sci ; 39(5): 719-726, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31612388

RESUMO

Hepatitis E virus (HEV) infection is a major cause of morbidity in endemic areas. Its consequences among chronic hepatitis B (CHB) patients have been under-reported. The aim of this study was to assess the impact of superinfective HEV infection (acute and past) on virological and clinical features of patients with CHB infection. Clinical, biochemical, virological and immunological data of 153 CHB patients including 98 with hepatitis B virus (HBV) monoinfection and 55 with HBV-HEV superinfection with both HEV and HBV infection was retrospectively investigated and analyzed in this study conducted in Wuhan, China. An overall anti-HEV IgG seroprevalence was found to be 35.9% in CHB patients. HBV-HEV superinfection patients showed significantly higher rate of complications (ascites, hepato-renal syndrome & encephalopathy) (all with P=0.04), cirrhosis (P<0.001) and acute-on-chronic liver failure (P<0.001) than HBV monoinfection patients. They also displayed elevated ALTs (P<0.001) and total serum bilirubin (P<0.001) with diminished albumin (P<0.001) and HBV viral load (P<0.001). Cytokines assay revealed increased expression of IL-6 (P=0.02), IL-10 (P=0.009) and TNF-α (P=0.003) in HBV-HEV superinfection patients compared to HBV monoinfection patients. Our study demonstrated that HEV superinfection in CHB patients was associated with progressive clinical manifestation, which is likely due to the enhanced expression of cytokines related with hepatocytes necrosis. HEV was also associated with repressed HBV replication, but the underlying mechanism requires further investigation.


Assuntos
Insuficiência Hepática Crônica Agudizada/virologia , Ascite/virologia , Encefalopatia Hepática/virologia , Hepatite B Crônica/virologia , Hepatite E/virologia , Síndrome Hepatorrenal/virologia , Cirrose Hepática/virologia , Superinfecção/virologia , Insuficiência Hepática Crônica Agudizada/complicações , Insuficiência Hepática Crônica Agudizada/imunologia , Insuficiência Hepática Crônica Agudizada/patologia , Adulto , Idoso , Alanina Transaminase/sangue , Alanina Transaminase/imunologia , Ascite/complicações , Ascite/imunologia , Ascite/patologia , Bilirrubina/sangue , Bilirrubina/imunologia , China , Feminino , Encefalopatia Hepática/complicações , Encefalopatia Hepática/imunologia , Encefalopatia Hepática/patologia , Anticorpos Anti-Hepatite/sangue , Vírus da Hepatite B/imunologia , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/complicações , Hepatite B Crônica/imunologia , Hepatite B Crônica/patologia , Hepatite E/complicações , Hepatite E/imunologia , Hepatite E/patologia , Vírus da Hepatite E/imunologia , Vírus da Hepatite E/patogenicidade , Hepatócitos/imunologia , Hepatócitos/patologia , Hepatócitos/virologia , Síndrome Hepatorrenal/complicações , Síndrome Hepatorrenal/imunologia , Síndrome Hepatorrenal/patologia , Humanos , Imunoglobulina G/sangue , Interleucina-10/sangue , Interleucina-10/imunologia , Interleucina-6/sangue , Interleucina-6/imunologia , Fígado/imunologia , Fígado/patologia , Fígado/virologia , Cirrose Hepática/complicações , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Superinfecção/complicações
6.
Nat Rev Gastroenterol Hepatol ; 16(10): 631-641, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31477873

RESUMO

Chronic hepatitis B virus (HBV) infection is a serious problem owing to its worldwide distribution and potential adverse sequelae that include cirrhosis and/or hepatocellular carcinoma. Current antiviral therapies have much improved outcomes, but few patients achieve the ultimate goal of hepatitis B surface antigen (HBsAg) loss (functional cure). As hepatitis B e antigen (HBeAg)-negative chronic HBV infection is the final phase prior to HBsAg loss, the management of patients in this phase together with quantification of HBsAg has attracted increasing clinical and research interest. This Review integrates the findings from research in HBsAg kinetics and discusses how they might inform our understanding and management of HBeAg-negative chronic HBV infection. Studies have shown that HBsAg levels are highly predictive of the presence of inactive HBV infection and that serial changes in HBsAg levels might predict HBsAg loss within 1-3 years. Data also suggest that quantitative HBsAg monitoring is important during hepatitis flare and antiviral therapy, especially in the timing of the decision to stop therapy and to start off-therapy retreatment. These findings have shed new light on the natural course of HBV infection and might lead to optimization of the management of HBeAg-negative chronic HBV infection and contribute to the paradigm shift from indefinite to finite therapy for patients with HBV infection.


Assuntos
Carcinoma Hepatocelular/virologia , Antígenos da Hepatite B/imunologia , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/imunologia , Cirrose Hepática/virologia , Neoplasias Hepáticas/virologia , Antivirais/uso terapêutico , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/prevenção & controle , Progressão da Doença , Antígenos de Superfície da Hepatite B/imunologia , Antígenos E da Hepatite B/imunologia , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Humanos , Cirrose Hepática/imunologia , Cirrose Hepática/prevenção & controle , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/prevenção & controle
7.
World J Gastroenterol ; 25(33): 4835-4849, 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31543677

RESUMO

Liver fibrosis is the common pathological basis of all chronic liver diseases, and is the necessary stage for the progression of chronic liver disease to cirrhosis. As one of pathogenic factors, inflammation plays a predominant role in liver fibrosis via communication and interaction between inflammatory cells, cytokines, and the related signaling pathways. Damaged hepatocytes induce an increase in pro-inflammatory factors, thereby inducing the development of inflammation. In addition, it has been reported that inflammatory response related signaling pathway is the main signal transduction pathway for the development of liver fibrosis. The crosstalk regulatory network leads to hepatic stellate cell activation and proinflammatory cytokine production, which in turn initiate the fibrotic response. Compared with the past, the research on the pathogenesis of liver fibrosis has been greatly developed. However, the liver fibrosis mechanism is complex and many pathways involved need to be further studied. This review mainly focuses on the crosstalk regulatory network among inflammatory cells, cytokines, and the related signaling pathways in the pathogenesis of chronic inflammatory liver diseases. Moreover, we also summarize the recent studies on the mechanisms underlying liver fibrosis and clinical efforts on the targeted therapies against the fibrotic response.


Assuntos
Mediadores da Inflamação/metabolismo , Inflamação/imunologia , Cirrose Hepática/imunologia , Fígado/patologia , Transdução de Sinais/imunologia , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Modelos Animais de Doenças , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/imunologia , Células Estreladas do Fígado/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/imunologia , Hepatócitos/metabolismo , Humanos , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/patologia , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/imunologia , Fígado/citologia , Fígado/imunologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Terapia de Alvo Molecular/métodos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinonas/farmacologia , Pirimidinonas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Ácido Ursodesoxicólico/análogos & derivados , Ácido Ursodesoxicólico/farmacologia , Ácido Ursodesoxicólico/uso terapêutico
8.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1864(12): 158526, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31520775

RESUMO

Although human adipose tissue-derived stromal vascular fraction (SVF) has been considered a promising source of stem cells, its characteristics relevant to treatment of a damaged liver have not been fully elucidated. In the present study, we sought to characterize the property of human SVF and determine the therapeutic utility of SVF in the liver cirrhosis model. We performed microarray, quantitative (q)-PCR experiments, and in vivo therapeutic assays using a liver cirrhotic mouse model. q-PCR results revealed that hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF)-A, Interleukin (IL)-10 and microRNA (miR)-146 were more highly upregulated in SVF than in human adipose-derived mesenchymal stem cells (ASCs). The SVF culture medium (CM) inhibited the activation of hepatic stellate cells in vitro. Injection of SVF significantly suppressed TAA-induced liver fibrosis and repaired liver function by inhibition of infiltrating inflammatory cells and induction of capillary/hepatocyte regeneration in vivo. Injection of IL-10 siRNA treated SVF cells decreased anti-inflammation and anti-fibrotic effects in TAA-induced mice liver. Our data indicate that SVF show a high anti-inflammatory property for treating fibrotic liver diseases through IL-10 secretion. Therefore, SVF might be a novel therapeutic alternative for the treatment of liver cirrhosis in clinical settings.


Assuntos
Inflamação/terapia , Cirrose Hepática/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/imunologia , Animais , Linhagem Celular , Células Cultivadas , Modelos Animais de Doenças , Fator de Crescimento de Hepatócito/análise , Fator de Crescimento de Hepatócito/imunologia , Humanos , Inflamação/imunologia , Inflamação/fisiopatologia , Interleucina-10/análise , Interleucina-10/imunologia , Fígado/imunologia , Fígado/fisiopatologia , Cirrose Hepática/imunologia , Cirrose Hepática/fisiopatologia , Masculino , Células-Tronco Mesenquimais/citologia , Camundongos Endogâmicos NOD , Camundongos SCID , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/imunologia
9.
World J Gastroenterol ; 25(28): 3684-3703, 2019 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-31391766

RESUMO

Acute kidney injury (AKI) is a common complication of liver cirrhosis and is of the utmost clinical and prognostic relevance. Patients with cirrhosis, especially decompensated cirrhosis, are more prone to develop AKI than those without cirrhosis. The hepatorenal syndrome type of AKI (HRS-AKI), a spectrum of disorders in prerenal chronic liver disease, and acute tubular necrosis (ATN) are the two most common causes of AKI in patients with chronic liver disease and cirrhosis. Differentiating these conditions is essential due to the differences in treatment. Prerenal AKI, a more benign disorder, responds well to plasma volume expansion, while ATN requires more specific renal support and is associated with substantial mortality. HRS-AKI is a facet of these two conditions, which are characterized by a dysregulation of the immune response. Recently, there has been progress in better defining this clinical entity, and studies have begun to address optimal care. The present review synopsizes the current diagnostic criteria, pathophysiology, and treatment modalities of HRS-AKI and as well as AKI in other chronic liver diseases (non-HRS-AKI) so that early recognition of HRS-AKI and the appropriate management can be established.


Assuntos
Lesão Renal Aguda/diagnóstico , Insuficiência Hepática Crônica Agudizada/complicações , Síndrome Hepatorrenal/diagnóstico , Cirrose Hepática/complicações , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/terapia , Insuficiência Hepática Crônica Agudizada/imunologia , Insuficiência Hepática Crônica Agudizada/patologia , Creatinina/sangue , Circulação Extracorpórea/instrumentação , Circulação Extracorpórea/métodos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Síndrome Hepatorrenal/etiologia , Síndrome Hepatorrenal/terapia , Humanos , Rim/irrigação sanguínea , Rim/imunologia , Rim/patologia , Fígado/imunologia , Fígado/patologia , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Transplante de Fígado , Fígado Artificial , Prognóstico , Índice de Gravidade de Doença , Resultado do Tratamento , Vasoconstritores/uso terapêutico
10.
World J Gastroenterol ; 25(27): 3527-3537, 2019 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-31367154

RESUMO

Hepatitis B virus (HBV) infection is one the leading risk factors for chronic hepatitis, liver fibrosis, cirrhosis and hepatocellular cancer (HCC), which are a major global health problem. A large number of clinical studies have shown that chronic HBV persistent infection causes the dysfunction of innate and adaptive immune response involving monocytes/macrophages, dendritic cells, natural killer (NK) cells, T cells. Among these immune cells, cell subsets with suppressive features have been recognized such as myeloid derived suppressive cells(MDSC), NK-reg, T-reg, which represent a critical regulatory system during liver fibrogenesis or tumourigenesis. However, the mechanisms that link HBV-induced immune dysfunction and HBV-related liver diseases are not understood. In this review we summarize the recent studies on innate and adaptive immune cell dysfunction in chronic HBV infection, liver fibrosis, cirrhosis, and HCC, and further discuss the potential mechanism of HBV-induced immunosuppressive cascade in HBV infection and consequences. It is hoped that this article will help ongoing research about the pathogenesis of HBV-related hepatic fibrosis and HBV-related HCC.


Assuntos
Vírus da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Tolerância Imunológica , Cirrose Hepática/imunologia , Neoplasias Hepáticas/imunologia , Carcinogênese/imunologia , Progressão da Doença , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Celular , Imunidade Inata , Fígado/imunologia , Fígado/patologia , Fígado/virologia , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia
11.
Int Immunopharmacol ; 75: 105816, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31437794

RESUMO

Docosahexaenoic acid (DHA) has been found to have a hepatoprotective effect. In this study, we investigated the role of peroxisome proliferator-activated receptor γ (PPARγ) in DHA regulation of liver fibrosis. DHA was found to inhibit hepatic stellate cell (HSC)-LX2 cell viability and downregulate marker proteins of HSC activation. Furthermore, DHA induced cell cycle arrest at G1 phase in HSCs. Antagonism of PPARγ by GW9662 abrogated the effects of DHA on HSCs. Computer-aided molecular docking predicted that DHA bound to PPARγ via hydrogen bonding with residues Ser289, His323, Tyr473, and His499. We overexpressed Ser289 mutant PPARγ in HSC-LX2 cells and investigated fibrotic marker modulation, and found that DHA effects on HSCs were diminished. Thus, bonding with the Ser289 residue might be indispensable for DHA to activate PPARγ to exert its inhibiting effect on activated HSCs. Last, data from a CCl4-treated mouse model confirmed that PPARγ activation was required for DHA to attenuate liver fibrosis.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/uso terapêutico , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/tratamento farmacológico , PPAR gama/imunologia , Animais , Tetracloreto de Carbono , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Ácidos Docosa-Hexaenoicos/farmacologia , Células Estreladas do Fígado/imunologia , Humanos , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Masculino , Camundongos Endogâmicos ICR
12.
PLoS One ; 14(7): e0215557, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31291257

RESUMO

BACKGROUND: Chronic inflammation is the driver of liver injury and results in progressive fibrosis and eventual cirrhosis with consequences including both liver failure and liver cancer. We have previously described increased expression of the highly multifunctional glycoprotein CD147 in liver injury. This work describes a novel role of CD147 in liver inflammation and the importance of leukocyte aggregates in determining the extent of liver injury. METHODS: Non-diseased, progressive injury, and cirrhotic liver from humans and mice were examined using a mAb targeting CD147. Inflammatory cell subsets were assessed by multiparameter flow cytometry. RESULTS: In liver injury, we observe abundant, intrahepatic leukocyte clusters defined as ≥5 adjacent CD45+ cells which we have termed "leukocyte aggregates". We have shown that these leukocyte aggregates have a significant effect in determining the extent of liver injury. If CD147 is blocked in vivo, these leukocyte aggregates diminish in size and number, together with a marked significant reduction in liver injury including fibrosis. This is accompanied by no change in overall intrahepatic leukocyte numbers. Further, blocking of aggregation formation occurs prior to an appreciable increase in inflammatory markers or fibrosis. Additionally, there were no observed, "off-target" or unpredicted effects in targeting CD147. CONCLUSION: CD147 mediates leukocyte aggregation which is associated with the development of liver injury. This is not a secondary effect, but a cause of injury as aggregate formation proceeds other markers of injury. Leukocyte aggregation has been previously described in inflammation dating back over many decades. Here we demonstrate that leukocyte aggregates determine the extent of liver injury.


Assuntos
Basigina/metabolismo , Leucócitos/imunologia , Fígado/imunologia , Fígado/lesões , Animais , Basigina/genética , Agregação Celular/imunologia , Hepatócitos/imunologia , Hepatócitos/patologia , Humanos , Leucócitos/classificação , Leucócitos/patologia , Fígado/patologia , Cirrose Hepática/genética , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/imunologia , Cirrose Hepática Experimental/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Regulação para Cima
13.
BMJ Case Rep ; 12(7)2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31352386

RESUMO

In the USA, mortality associated with hepatocellular carcinoma (HCC) continues to rise. Globally, HCC is the third most common cause of cancer-related death. In early stages of HCC, hepatic resection or liver transplantation are the preferred treatment options with a high probability of recurrence-free postoperative course. However, ineffective screening of chronic liver diseases in high-risk populations, poor linkage to care and suboptimal HCC surveillance has led to increasing rates of late-stage HCC at clinical presentation or diagnosis amenable only to palliative and experimental treatment options. Our case is a 66-year-old man with chronic hepatitis C virus infection complicated by cirrhosis and inoperable HCC which was non-responsive to selective intrahepatic trans-arterial chemoembolisation by interventional radiology. Therefore, he was treated with nivolumab immunotherapy and demonstrated normalisation of previously elevated alpha-fetoprotein levels suggestive of at least a partial response to immunotherapy. No adverse events related to nivolumab immunotherapy were encountered.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Imunoterapia , Cirrose Hepática/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , alfa-Fetoproteínas/efeitos dos fármacos , Idoso , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Hepatite C Crônica/imunologia , Hepatite C Crônica/patologia , Humanos , Fatores Imunológicos/uso terapêutico , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Masculino , Nivolumabe/uso terapêutico , Prognóstico , Resultado do Tratamento , alfa-Fetoproteínas/metabolismo
14.
Int Immunopharmacol ; 75: 105765, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31336335

RESUMO

Hepatic fibrosis is the most common pathological feature of most chronic liver diseases, and its continuous deterioration gradually develops into liver cirrhosis and eventually leads to liver cancer. At present, there are many kinds of drugs used to treat liver fibrosis. However, Western drugs tend to only target single genes/proteins and induce many adverse reactions. Most of the mechanisms and active ingredients of traditional Chinese medicine (TCM) are not clear, and there is a lack of unified diagnosis and treatment standards. Natural products, which are characterized by structural diversity, low toxicity, and origination from a wide range of sources, have unique advantages and great potential in anti-liver fibrosis. This article summarizes the work done over the previous decade, on the active ingredients in natural products that are reported to have anti-hepatic fibrosis effects. The effective anti-hepatic fibrosis ingredients identified can be generally divided into flavonoids, saponins, polysaccharides and alkaloids. Mechanisms of anti-liver fibrosis include inhibition of liver inflammation, anti-lipid peroxidation injury, inhibition of the activation and proliferation of hepatic stellate cells (HSCs), modulation of the synthesis and secretion of pro-fibrosis factors, and regulation of the synthesis and degradation of the extracellular matrix (ECM). This review provides suggestions for the development of anti-hepatic fibrosis drugs.


Assuntos
Produtos Biológicos/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Animais , Produtos Biológicos/farmacologia , Humanos , Cirrose Hepática/imunologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia
15.
PLoS Negl Trop Dis ; 13(6): e0007474, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31194740

RESUMO

During Schistosoma infection, lack of B cells results in more severe granulomas, inflammation, and fibrosis in the liver, but the mechanisms underlying this pathology remain unclear. This study was to clarify the mechanisms underpinning the immunomodulation of B cells in mice infected with Schistosoma japonicum (S. japonicum). We found that B cell deficiency led to aggravated liver pathology, as demonstrated by increases in the size of the egg-associated granulomas, alanine transaminase levels, and collagen deposition. Compared with infected wild-type (WT) mice, infected B cell-deficient (µMT) mice showed increased infiltration of Ly6Chi monocytes and higher levels of proinflammatory cytokines and chemokines. Furthermore, B1 cells were increased significantly in the liver of WT mice following S. japonicum infection. Adoptively transferring B1 cells, but not B2 cells, to µMT mice significantly reduced liver pathology and liver infiltration of Ly6Chi monocytes. Additionally, secretion of IL-10 from hepatic B cells increased significantly in infected WT mice and this IL-10 was mainly derived from B1 cells. Adoptively transferring B1 cells purified from WT mice, but not from IL-10-deficient mice, to µMT mice significantly reduced liver pathology and liver infiltration of Ly6Chi monocytes. These reductions were accompanied by decreases in the expression levels of chemokines and inflammatory cytokines. Taken together, these data indicated that after S. japonicum infection, an increased number of hepatic B1 cells secrete IL-10, which inhibits the expression of chemokines and cytokines and suppresses the infiltration of Ly6Chi monocytes into the liver thereby alleviating liver early inflammation and late fibrosis.


Assuntos
Linfócitos B/imunologia , Hepatite/complicações , Hepatite/prevenção & controle , Cirrose Hepática/prevenção & controle , Monócitos/imunologia , Schistosoma japonicum/imunologia , Esquistossomose Japônica/complicações , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Hepatite/imunologia , Fatores Imunológicos/metabolismo , Cirrose Hepática/imunologia , Masculino , Camundongos Endogâmicos C57BL
16.
J Immunol Res ; 2019: 3538963, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31205954

RESUMO

Humanized mouse models can well be modified to study specific aspects of Graft-versus-Host Disease (GvHD). This paper shows the results of both macrophage depletion and (early) B-cell depletion in a humanized mouse model using RAG2-/- γc-/- mice injected with HuPBMCs. Macrophage depletion showed a significant decrease in survival and also lead to a change in the histomorphology of the xenogeneic reaction. Higher levels of infiltrating B-cells were observed in various organs of mice depleted for macrophages. With (early) B-cell depletion using Rituximab, a clear improvement on clinical symptoms was observed, even when probably only inactivated B-cells were deleted. However, the histological examinations only showed a significant morphological effect on liver fibrosis. This may be related to a difference in the mRNA levels of TGF-ß. Also, lower mRNA levels of Tregs in some organs were observed after Rituximab treatment, which contradicts that a higher number of Tregs would always be related to less severe GvHD. Our data show that both macrophage depletion and (early) B-cell depletion in a xenogeneic mouse model can influence the clinical, histological, and cytokine production of a GvHD response.


Assuntos
Linfócitos B/imunologia , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas , Leucócitos Mononucleares/imunologia , Cirrose Hepática/imunologia , Macrófagos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Modelos Animais de Doenças , Feminino , Humanos , Depleção Linfocítica , Camundongos , Camundongos SCID
17.
Folia Histochem Cytobiol ; 57(2): 74-83, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31187872

RESUMO

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease which becomes a rapidly growing health problem in the Western countries. The development of the disease is most often connected to obesity. NAFLD is also considered as the hepatic manifestation of metabolic syndrome. Transforming growth factor b1 (TGF-b1) plays an important role in the pathogenesis of liver fibrosis, being involved in activation of hepatic stellate cells, stimulation of collagen gene transcription, and suppression of matrix metalloproteinase expression. The objective of the study was to evaluate by immunohistochemistry the expression of TGF-b1 in the liver tissue of NAFLD patients and correlate it with anthropometric, biochemical and routine histological parameters. MATERIAL AND METHODS: The study group consisted of 48 patients with diagnosed NAFLD. Liver steatosis, NAFLD Activity Score (NAS) and METAVIR score of fibrosis were evaluated in liver biopsies. The immunoreactivity of TGF-b1 was evaluated semi-quantitatively separately in portal, septal, lobular hepatocytic and lobular sinu-soidal liver compartments. The results were analyzed in regard to patients' clinical and biochemical parameters. RESULTS: Neither steatosis nor NAS correlated with TGF-b1 expression in any liver compartment, whereas METAVIR score of fibrosis was associated with increased immunoreactivity of TGF-b1 in most of the studied liver compartments. TGF-b1 immunoreactivity showed positive correlation with patients' age and its expression in septal compartment disclosed positive correlation with body mass index, and waist and hip circumference. Hyaluronic acid serum level was positively and iron concentration was negatively associated with TGF-b1 ex-pression in the selected consecutive liver compartments. CONCLUSIONS: The immunohistochemical expression of TGF-b1 may be complementary to routine methods of liver fibrosis evaluation.


Assuntos
Cirrose Hepática/imunologia , Fígado/imunologia , Hepatopatia Gordurosa não Alcoólica/imunologia , Fator de Crescimento Transformador beta1/imunologia , Adulto , Peptídeo C/sangue , Fígado Gorduroso/patologia , Feminino , Hemoglobina A Glicada/análise , Haptoglobinas/análise , Humanos , Ácido Hialurônico/sangue , Imuno-Histoquímica , Ferro/sangue , Fígado/patologia , Cirrose Hepática/diagnóstico , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/patologia , Fator de Crescimento Transformador beta1/sangue
18.
Int J Med Sci ; 16(5): 720-728, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31217740

RESUMO

Objective: This study aims to clarify the changes and clinical significance of red cell distribution width (RDW) during HBV-related chronic diseases, including inactive hepatitis B virus (HBV) carriers, HBV immune tolerant individuals, chronic hepatitis B (CHB) patients and HBV-related hepatocirrhosis patients. Methods: RDW was measured 288 CHB patients, 100 patients with hepatitis B e antigen(HBeAg)-negative chronic HBV infection (inactive carriers), 92 patients with HBeAg-positive chronic HBV infection (immune tolerant), and 272 patients with HBV-related hepatocirrhosis. Their RDW changes were compared with 160 healthy controls. Correlations between RDW and clinical indicators were conducted. For HBeAg+ CHB patients, RDW was measured before and after antiviral therapy. The efficiency of RDW to distinguish hepatocirrhosis from CHB and/or inactive carriers was evaluated by receiver operating characteristic (ROC) curves. Results: RDW was higher in hepatocirrhosis patients than other groups of patients and healthy controls. Besides, HBeAg+ CHB patients possessed higher RDW than HBeAg- CHB patients. For HBeAg+ patients that underwent HBeAg seroconversion after antiviral therapy, RDW was decreased. RDW was positively correlated with total bilirubin and Child-Pugh scores and negatively correlated with albumin among hepatocirrhosis patients. The areas under the curve (AUC) of ROC curves to distinguish hepatocirrhosis from CHB patients was 0.7040 for RDW-standard deviation (RDW-SD) and 0.6650 for RDW-coefficient of variation (RDW-CV), and AUC to distinguish hepatocirrhosis from inactive carriers was 0.7805 for RDW-SD and 0.7991 for RDW-CV. Conclusions: RDW is significantly increased in HBeAg+ CHB patients and patients with HBV-related hepatocirrhosis and could reflect their severity. RDW could help to distinguish hepatocirrhosis from CHB patients and inactive HBV carriers.


Assuntos
Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/sangue , Cirrose Hepática/sangue , Adulto , Diagnóstico Diferencial , Índices de Eritrócitos/imunologia , Feminino , Antígenos E da Hepatite B/imunologia , Vírus da Hepatite B/imunologia , Vírus da Hepatite B/metabolismo , Hepatite B Crônica/imunologia , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Humanos , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade
19.
Immunopharmacol Immunotoxicol ; 41(3): 438-445, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31119954

RESUMO

Objective: Paeonol is a natural phenolic component isolated from the root bark of peony with multiple pharmacological activities. We investigated the anti-fibrotic effect and underlying mechanism of paeonol. Methods: Twenty-four male C57BL/6J mice were divided into 4 groups (n = 6 in each group), injected with CCl4 to induce liver fibrosis and administrated with paeonol according to the regimen. The serum activity of ALT and AST, and H&E staining were to assess liver injury. Sirius and Masson staining, and hydroxyproline content were to evaluate the degree of liver fibrosis. TNF-α, IL-6, TGF-ß, MDA, GSH-PX, SOD, and CAT were detected to reflect inflammation and oxidative stress. RT-qPCR and Western blot analysis to assess the activation of HSCs and TGF-ß/Smad3 signaling. Results: Paeonol ameliorated liver injury and liver fibrosis, reflected by the decrease of ALT, AST, less lesion in H&E staining, mitigated fibrosis in Sirius and Masson staining, lessened content of hydroxyproline. Paeonol attenuated the level of IL-6 and TNF-α, and elevated the activity of GSH-PX, SOD, and CAT with reducing the level of MDA. The expression of col 1a, α-SMA, vimentin, and desmin were down-regulated and TGF-ß/Smad3 signaling pathway was inhibited. Conclusion: These data demonstrated that paeonol could alleviate CCl4-induced liver fibrosis through suppression of hepatic stellate cells activation via inhibiting the TGF-ß/Smad3 signaling.


Assuntos
Acetofenonas/farmacologia , Intoxicação por Tetracloreto de Carbono/tratamento farmacológico , Células Estreladas do Fígado/imunologia , Cirrose Hepática/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3/imunologia , Fator de Crescimento Transformador beta/imunologia , Animais , Intoxicação por Tetracloreto de Carbono/imunologia , Intoxicação por Tetracloreto de Carbono/patologia , Células Estreladas do Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Masculino , Camundongos , Transdução de Sinais/imunologia
20.
Anticancer Res ; 39(4): 2183-2191, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30952766

RESUMO

AIM: We previously reported that sorafenib induces Th1 [interferon-γ (IFNγ)-positive interleukin 4 (IL4)-negative] dominance which prevents tumor cells from escaping the host immune system in patients with liver cirrhosis (LC) and advanced hepatocellular carcinoma (aHCC). However, in that study we did not assess the influence of sorafenib on host immunity according to the etiology of LC. Therefore, this study was retrospectively performed to evaluate the impact of sorafenib therapy for aHCC on host immunity in patients stratified according to the etiology of LC: Patients and Methods: A total of 116 adult Japanese patients with LC and aHCC received sorafenib therapy at our hospital. Blood samples were collected before and after treatment for 4 weeks. RESULTS: Twenty-two patients had hepatitis B virus (HBV)-related LC, 62 patients had hepatitis C virus (HCV)-related LC, 22 patients had alcoholic LC, and 10 patients had LC without these causative factors. In patients receiving sorafenib at a dose of 400 mg/day, patients in Child-Pugh class A, and patients with stage IVA aHCC, Th2 (IFNγ-negative/IL4-positive) cells decreased significantly after treatment, although there was no significant impact on the tumor response. In addition, Th2 cells decreased significantly in patients with HCV-related LC after treatment, while there were no significant changes in the other groups. CONCLUSION: Sorafenib might prevent tumor cells from escaping the host immune system in patients with aHCC and HCV-related LC, although it does not seem to do so in those with LC of other etiologies.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/imunologia , Cirrose Hepática/imunologia , Neoplasias Hepáticas/imunologia , Inibidores de Proteínas Quinases/farmacologia , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/etiologia , Feminino , Hepatite B/complicações , Hepatite C/complicações , Humanos , Interferon gama/imunologia , Interleucina-4/imunologia , Cirrose Hepática/etiologia , Neoplasias Hepáticas/etiologia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Sorafenibe , Células Th2/imunologia
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