scholarly journals Inhibition of Rho-Kinase Downregulates Th17 Cells and Ameliorates Hepatic Fibrosis by Schistosoma japonicum Infection

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1262 ◽  
Author(s):  
Wei Zhou ◽  
Yingying Yang ◽  
Congjin Mei ◽  
Panpan Dong ◽  
Shasha Mu ◽  
...  
Keyword(s):  
Schistosoma Japonicum ◽  
Hepatic Fibrosis ◽  
Hepatic Stellate Cells ◽  
Th17 Cells ◽  
Worm Burden ◽  
Molecular Mechanisms ◽  
Stellate Cells ◽  
Granuloma Formation ◽  
Type I ◽  
Hepatic Granuloma

Background: Schistosomiasis is an immunopathogenic disease in which Th17 cells play vital roles. Hepatic granuloma formation and subsequent fibrosis are its main pathologic manifestations and the leading causes of hepatic cirrhosis, and effective therapeutic interventions are lacking. In this study, we explored the effects of fasudil, a selective RhoA–Rho-associated kinase (ROCK) inhibitor, on Th17 cells and the pathogenesis of schistosomiasis. Methods: Mice were infected with Schistosoma japonicum and treated with fasudil. The worm burden, hepatic granuloma formation, and fibrosis were evaluated. The roles of fasudil on Th17, Treg, and hepatic stellate cells were analyzed. Results: Fasudil therapy markedly reduced the granuloma size and collagen deposit in livers from mice infected with S. japonicum. However, fasudil therapy did not affect the worm burden in infected mice. The underlying cellular and molecular mechanisms were investigated. Fasudil suppressed the activation and induced the apoptosis of CD4+ T cells. Fasudil inhibited the differentiation and effector cytokine secretion of Th17 cells, whereas it upregulated Treg cells in vitro. It also restrained the in vivo interleukin (IL)-4 and IL-17 levels in infected mice. Fasudil directly induced the apoptosis of hepatic stellate cells and downregulated the expressions of hepatic fibrogenic genes, such as collagen type I (Col-I), Col-III, and transforming growth factor-1 (TGF-β1). These effects may contribute to its anti-pathogenic roles in schistosomiasis. Conclusions: Fasudil inhibits hepatic granuloma formation and fibrosis with downregulation of Th17 cells. Fasudil might serve as a novel therapeutic agent for hepatic fibrosis due to schistosome infections and perhaps other disorders.

scholarly journals Suberoylanilide hydroxamic acid suppresses hepatic stellate cells activation by HMGB1 dependent reduction of NF-κB1

PeerJ ◽  
2015 ◽  
Vol 3 ◽  
pp. e1362 ◽  
Author(s):  
Wenwen Wang ◽  
Min Yan ◽  
Qiuhong Ji ◽  
Jinbiao Lu ◽  
Yuhua Ji ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Hydroxamic Acid ◽  
Molecular Mechanisms ◽  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
Cdna Array ◽  
Stellate Cells ◽  
Type I ◽  
Suberoylanilide Hydroxamic Acid

Hepatic stellate cells (HSCs) activation is essential to the pathogenesis of liver fibrosis. Exploring drugs targeting HSC activation is a promising anti-fibrotic strategy. In the present study, we found suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, prominently suppressed the activation phenotype of a human hepatic stellate cell line—LX2. The production of collagen type I andα-smooth muscle actin (α-SMA) as well as the proliferation and migration of LX2 cells were significantly reduced by SAHA treatment. To determine the molecular mechanisms underlying this suppression, genome wild gene regulation by SAHA was determined by Affymetrix 1.0 human cDNA array. Upon SAHA treatment, the abundance of 331 genes was up-regulated and 173 genes was down-regulated in LX2 cells. Bioinformatic analyses of these altered genes highlighted the high mobility group box 1 (HMGB1) pathway was one of the most relevant pathways that contributed to SAHA induced suppression of HSCs activation. Further studies demonstrated the increased acetylation of intracellular HMGB1 in SAHA treated HSCs, and this increasing is most likely to be responsible for SAHA induced down-regulation of nuclear factor kappa B1 (NF-κB1) and is one of the main underlying mechanisms for the therapeutic effect of SAHA for liver fibrosis.

scholarly journals Fuzheng Huayu Capsule Attenuates Hepatic Fibrosis by Inhibiting Activation of Hepatic Stellate Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Mei Wu ◽  
Yang Zhou ◽  
Sheng-Lan Qin ◽  
Li-Jing Lin ◽  
Jian Ping ◽  
...  
Keyword(s):  
Treatment Group ◽  
Hepatic Fibrosis ◽  
Hepatic Stellate Cells ◽  
Killer Cell ◽  
Liver Stiffness ◽  
Stellate Cells ◽  
Type I ◽  
Procollagen Type ◽  
Procollagen Type I ◽  
Injury Models

Aim. To investigate the mechanisms of Fuzheng Huayu (FZHY) Capsule in the treatment of hepatitis B (HBV)- associated fibrosis, HBV patients were divided into two groups, 50 cases were in the nucleotide analogues (NAs) group, while additional 50 cases were in the NAs + FZHY group. Methods. We assessed the curative effects of antifibrosis through liver function, FibroScan test, and liver biopsy and detected the ratio of lymphocyte subsets by flow cytometry. Peripheral blood lymphocyte and CD8+T, CD4+T, and natural killer cell subsets collected from patients were cocultured with LX-2 cells. Activation of LX-2 cells, production of the extracellular matrix, apoptosis, and proliferation of LX-2 cells were determined. Chronic liver injury models were established by ConA treatment. Results. It is evident that FZHY treatment significantly increased the percentage of NK cells, the rate of death, and apoptosis of LX-2 cells and decreased the FibroScan liver stiffness measurement value. The expressions of α-SMA and procollagen type I mRNA in LX-2 cells of the FZHY treatment group as downregulated when they were cocultured with lymphocytes compared to those from the NAs group. The proliferation of LX-2 cells in the FZHY treatment group was inhibited compared to that in the NAs group. In a mouse model of hepatic fibrosis, PBLs and IHLs from ConA exposure plus FZHY treatment inhibited the ability of JS-1 cells to express α-SMA. Conclusions. FZHY Capsule improved the disordered cellular immunity and postponed liver fibrosis possibly through inhibiting the interaction between lymphocyte and hepatic stellate cells.

Involvement of TLR4 Signaling Regulated-COX2/PGE2 Axis in Liver Fibrosis Induced by Schistosoma japonicum Infection

2021 ◽  
Author(s):  
Lan Chen ◽  
Xiaofang Ji ◽  
Manni Wang ◽  
Xiaoyan Liao ◽  
Cuiying Liang ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Schistosoma Japonicum ◽  
Hepatic Stellate Cells ◽  
Hepatitis Virus ◽  
Stellate Cells ◽  
Type I ◽  
Tlr4 Signaling ◽  
Pathway Activation ◽  
Mice Liver

Abstract Background: The hepatic stellate cells (HSCs) activation plays pivotal role in hepatic inflammation and liver fibrosis.TLR4 pathway activation has been reported to be involved in mice liver fibrosis induced by hepatitis virus infection, alcohol abuse, biliary ligation, carbon tetrachloride 4 treatment and Schistosoma japonicum (Sj) infection. The effect and mechanisms of cyclooxygenase 2 (COX2)/prostanoid E2 (PGE2) axis on liver fibrosis induced by Sj are still unclear. Results: This study investigated the link between COX2/PGE2 axis and TLR4 signaling in the induction of liver fibrogenesis in mice during Sj infection and in vitro culturing hepatic stellate cells (HSCs) strain-LX-2. The COX2/PGE2 axis was positively related with Sj-induced liver fibrosis. TLR4 pathway activation stimulated the COX2/PGE2 axis, in Sj-infected mice andin lipopolysaccharide (LPS)-exposed cultured HSCs. Synthetic PGE2 activated culturing HSCs through up-regulating alpha smooth muscle actin (α-SMA) expression. In LPS-triggered HSCs, NS398, a COX2 inhibitor led to suppression of PGE2 synthesis and reduced expression of α-SMA and type I collagen (COL I). Conclusions: These results indicated firstly the positive association of COX2/PGE2 axis with liver fibrosis induced by Sj infection. TLR4 signaling may control COX2/PGE2 axis in Sj-infected mice liver and in vitro culturing HSCs at least partially. COX2/PGE2-EP2/EP4 axis might be good drug targets against liver fibrosis induced by Sj infection.

scholarly journals Structural changes and expression of hepatic fibrosis-related proteins in coculture of Echinococcus multilocularis protoscoleces and human hepatic stellate cells

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Deping Cao ◽  
Emad Shamsan ◽  
Bofan Jiang ◽  
Haining Fan ◽  
Yaogang Zhang ◽  
...  
Keyword(s):  
Hepatic Fibrosis ◽  
Western Blotting ◽  
Hepatic Stellate Cells ◽  
Echinococcus Multilocularis ◽  
Structural Changes ◽  
Molecular Mechanisms ◽  
Morphological Changes ◽  
Stellate Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Related Proteins

Abstract Background Echinococcus multilocularis is the causative agent of human hepatic alveolar echinococcosis (AE). AE can cause damage to several organs, primarily the liver, and have severe outcomes, such as hepatic failure and encephalopathy. The main purpose of this study was to explore the interactions between hepatic stellate cells (HSCs) and E. multilocularis protoscoleces (PSCs). The results of this study provide an experimental basis for further examination of the pathogenesis of hepatic fibrosis due to AE infection. Methods We investigated the role of Echinococcus multilocularis (Echinococcus genus) PSCs in hepatic fibrosis by examining structural changes and measuring hepatic fibrosis-related protein levels in cocultures of PSCs and human HSCs. Structural changes were detected by transmission electron microscopy (TEM), and levels of the hepatic fibrosis-related proteins collagen I (Col-I), alpha-smooth muscle actin (α-SMA) and osteopontin (OPN) were measured by western blotting and enzyme-linked immunosorbent assay (ELISA). Results Under coculture (1) both PSCs and HSCs exhibited morphological changes, as observed by TEM; (2) Col-I, α-SMA, and OPN expression levels, which were determined by western blotting and ELISA, significantly increased after 3 days of incubation. Conclusions The results of this study provide insights into the molecular mechanisms of AE-induced hepatic fibrosis. Graphical abstract

scholarly journals Inhibitory effect of oestradiol on activation of rat hepatic stellate cells in vivo and in vitro

Gut ◽  
1999 ◽  
Vol 44 (1) ◽  
pp. 127-136 ◽  
Author(s):  
I Shimizu ◽  
Y Mizobuchi ◽  
M Yasuda ◽  
M Shiba ◽  
Y-R Ma ◽  
...  
Keyword(s):  
Hepatic Fibrosis ◽  
Hepatic Stellate Cells ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Inhibitory Effect ◽  
Type I ◽  
Mrna Levels ◽  
Pig Serum

BackgroundHepatic stellate cells play a key role in the pathogenesis of hepatic fibrosis.AimsTo examine the inhibitory effect of oestradiol on stellate cell activation.MethodsIn vivo, hepatic fibrosis was induced in rats by dimethylnitrosamine or pig serum. In vitro, rat stellate cells were activated by contact with plastic dishes resulting in their transformation into myofibroblast-like cells.ResultsIn the dimethylnitrosamine and pig serum models, treatment with oestradiol at gestation related doses resulted in a dose dependent suppression of hepatic fibrosis with restored content of hepatic retinyl palmitate, reduced collagen content, lower areas of stellate cells which express α smooth muscle actin (α-SMA) and desmin, and lower procollagen type I and III mRNA levels in the liver. In cultured stellate cells, oestradiol inhibited type I collagen production, α-SMA expression, and cell proliferation. These findings suggest that oestradiol is a potent inhibitor of stellate cell transformation.ConclusionThe antifibrogenic role of oestradiol in the liver may contribute to the sex associated differences in the progression from hepatic fibrosis to cirrhosis.

scholarly journals Cellular and Molecular Mechanisms of Hepatic Fibrosis

2015 ◽  
Vol 4 (3) ◽  
pp. 10
Author(s):  
Minling Cao ◽  
Xiaoling Chi ◽  
Junmin Jiang ◽  
Guangjun Tian
Keyword(s):  
Extracellular Matrix ◽  
Hepatic Fibrosis ◽  
Hepatic Stellate Cells ◽  
Molecular Mechanisms ◽  
Stellate Cells ◽  
Liver Cells ◽  
Tissue Factors

<p>The occurrence of hepatic fibrosis is a multi-factor involved process. The key is the activation of hepatic stellate cells (HSC). Synthesis of extracellular matrix in the liver cells increases while degradation decreases. This paper reviews the tissue factors and the mechanism closely related to the forming of hepatic fibrosis.</p>

Norepinephrine induces calcium spikes and proinflammatory actions in human hepatic stellate cells

2006 ◽  
Vol 291 (5) ◽  
pp. G877-G884 ◽  
Author(s):  
Pau Sancho-Bru ◽  
Ramón Bataller ◽  
Jordi Colmenero ◽  
Xavier Gasull ◽  
Montserrat Moreno ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Portal Hypertension ◽  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Stellate Cells ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Cell Contraction

Catecholamines participate in the pathogenesis of portal hypertension and liver fibrosis through α1-adrenoceptors. However, the underlying cellular and molecular mechanisms are largely unknown. Here, we investigated the effects of norepinephrine (NE) on human hepatic stellate cells (HSC), which exert vasoactive, inflammatory, and fibrogenic actions in the injured liver. Adrenoceptor expression was assessed in human HSC by RT-PCR and immunocytochemistry. Intracellular Ca2+ concentration ([Ca2+]i) was studied in fura-2-loaded cells. Cell contraction was studied by assessing wrinkle formation and myosin light chain II (MLC II) phosphorylation. Cell proliferation and collagen-α1(I) expression were assessed by [3H]thymidine incorporation and quantitative PCR, respectively. NF-κB activation was assessed by luciferase reporter gene and p65 nuclear translocation. Chemokine secretion was assessed by ELISA. Normal human livers expressed α1A-adrenoceptors, which were markedly upregulated in livers with advanced fibrosis. Activated human HSC expressed α1A-adrenoceptors. NE induced multiple rapid [Ca2+]i oscillations (Ca2+ spikes). Prazosin (α1-blocker) completely prevented NE-induced Ca2+ spikes, whereas propranolol (nonspecific β-blocker) partially attenuated this effect. NE caused phosphorylation of MLC II and cell contraction. In contrast, NE did not affect cell proliferation or collagen-α1(I) expression. Importantly, NE stimulated the secretion of inflammatory chemokines (RANTES and interleukin-8) in a dose-dependent manner. Prazosin blocked NE-induced chemokine secretion. NE stimulated NF-κB activation. BAY 11-7082, a specific NF-κB inhibitor, blocked NE-induced chemokine secretion. We conclude that NE stimulates NF-κB and induces cell contraction and proinflammatory effects in human HSC. Catecholamines may participate in the pathogenesis of portal hypertension and liver fibrosis by targeting HSC.

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