Aspirin induces autophagy and alleviates liver fibrosis by reducing oxidative stress and inflammation in mice model of chronic liver injury

Liver fibrosis is the common scarring reaction associated with chronic liver injury that results from prolonged parenchymal cell injury and/or inflammation. The fibrogenic response is characterized by progressive accumulation of extracellular matrix components enriched in fibrillar collagens and a failure of matrix turnover. This process is driven by a heterogeneous population of hepatic myofibroblasts, which mainly derive from hepatic stellate cells and portal fibroblasts. Regression of fibrosis can be achieved by the successful control of chronic liver injury, owing to termination of the fibrogenic reaction following clearance of hepatic myofibroblasts and restoration of fibrolytic pathways. Understanding of the complex network underlying liver fibrogenesis has allowed the identification of a large number of antifibrotic targets, but no antifibrotic drug has as yet been approved. This review will highlight recent advances regarding the mechanisms that regulate liver fibrogenesis and fibrosis regression, with special focus on novel signaling pathways and the role of inflammatory cells. Translation of these findings to therapies will require continued efforts to develop multitarget therapeutic approaches that will improve the grim prognosis of liver cirrhosis.

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Baihe Wuyao decoction ameliorates CCl4-induced chronic liver injury and liver fibrosis in mice through blocking TGF-β1/Smad2/3 signaling, anti-inflammation and anti-oxidation effects

Journal of Ethnopharmacology ◽

10.1016/j.jep.2020.113227 ◽

2020 ◽

Vol 263 ◽

pp. 113227

Author(s):

Yajing Chen ◽

Ruofei Li ◽

Nan Hu ◽

Chunping Yu ◽

Hongyu Song ◽

...

Keyword(s):

Liver Fibrosis ◽

Liver Injury ◽

Chronic Liver ◽

Chronic Liver Injury ◽

Anti Inflammation ◽

Tgf Β1

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Liver fibrosis is driven by protease‐activated receptor‐1 expressed by hepatic stellate cells in experimental chronic liver injury

Research and Practice in Thrombosis and Haemostasis ◽

10.1002/rth2.12403 ◽

2020 ◽

Vol 4 (5) ◽

pp. 906-917

Author(s):

Lauren G. Poole ◽

Asmita Pant ◽

Holly M. Cline‐Fedewa ◽

Kurt J. Williams ◽

Bryan L. Copple ◽

...

Keyword(s):

Liver Fibrosis ◽

Liver Injury ◽

Hepatic Stellate Cells ◽

Stellate Cells ◽

Chronic Liver ◽

Chronic Liver Injury ◽

Protease Activated Receptor 1

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Hepatic Stellate Cell–Macrophage Crosstalk in Liver Fibrosis and Carcinogenesis

Seminars in Liver Disease ◽

10.1055/s-0040-1708876 ◽

2020 ◽

Vol 40 (03) ◽

pp. 307-320

Author(s):

Michitaka Matsuda ◽

Ekihiro Seki

Keyword(s):

Liver Fibrosis ◽

Liver Injury ◽

Cell Activation ◽

Stellate Cell ◽

Tumor Development ◽

Mesenchymal Cell ◽

Chronic Liver ◽

Health Concern ◽

Chronic Liver Injury ◽

Fibrotic Liver

AbstractChronic liver injury due to viral hepatitis, alcohol abuse, and metabolic disorders is a worldwide health concern. Insufficient treatment of chronic liver injury leads to fibrosis, causing liver dysfunction and carcinogenesis. Most cases of hepatocellular carcinoma (HCC) develop in the fibrotic liver. Pathological features of liver fibrosis include extracellular matrix (ECM) accumulation, mesenchymal cell activation, immune deregulation, and angiogenesis, all of which contribute to the precancerous environment, supporting tumor development. Among liver cells, hepatic stellate cells (HSCs) and macrophages play critical roles in fibrosis and HCC. These two cell types interplay and remodel the ECM and immune microenvironment in the fibrotic liver. Once HCC develops, HCC-derived factors influence HSCs and macrophages to switch to protumorigenic cell populations, cancer-associated fibroblasts and tumor-associated macrophages, respectively. This review aims to summarize currently available data on the roles of HSCs and macrophages in liver fibrosis and HCC, with a focus on their interaction.

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LC3-associated phagocytosis protects against inflammation and liver fibrosis via immunoreceptor inhibitory signaling

Science Translational Medicine ◽

10.1126/scitranslmed.aaw8523 ◽

2020 ◽

Vol 12 (539) ◽

pp. eaaw8523 ◽

Cited By ~ 4

Author(s):

JingHong Wan ◽

Emmanuel Weiss ◽

Sanae Ben Mkaddem ◽

Morgane Mabire ◽

Pierre-Marie Choinier ◽

...

Keyword(s):

Liver Fibrosis ◽

Liver Injury ◽

Systemic Inflammation ◽

Multiorgan Failure ◽

Chronic Liver ◽

Human Monocytes ◽

Macrophage Phenotype ◽

Chronic Liver Injury ◽

Inflammatory Profile ◽

Inhibitory Signaling

Sustained hepatic and systemic inflammation, particularly originating from monocytes/macrophages, is a driving force for fibrosis progression to end-stage cirrhosis and underlies the development of multiorgan failure. Reprogramming monocyte/macrophage phenotype has emerged as a strategy to limit inflammation during chronic liver injury. Here, we report that LC3-associated phagocytosis (LAP), a noncanonical form of autophagy, protects against hepatic and systemic inflammation during chronic liver injury in rodents, with beneficial antifibrogenic effects. LAP is enhanced in blood and liver monocytes from patients with fibrosis and cirrhosis. Pharmacological inhibition of LAP components in human monocytes from patients with cirrhosis or genetic disruption of LAP in mice with chronic liver injury exacerbates both the inflammatory signature in isolated human monocytes and the hepatic inflammatory profile in mice, resulting in enhanced liver fibrosis. Mechanistically, patients with cirrhosis showed increased monocyte expression of Fc fragment of IgG receptor IIA (FcγRIIA) and enhanced engulfment of immunoglobulin G in LC3+ phagosomes that triggers an FcγRIIA/Src homology region 2 domain–containing phosphatase-1 (SHP-1) inhibitory immunoreceptor tyrosine-based activation motif (ITAMi) anti-inflammatory pathway. Mice overexpressing human FcγRIIA in myeloid cells show enhanced LAP in response to chronic liver injury and resistance to inflammation and liver fibrosis. Activation of LAP is lost in monocytes from patients with multiorgan failure and restored by specifically targeting ITAMi signaling with anti-FcγRIIA F(ab′)2 fragments, or with intravenous immunoglobulin (IVIg). These data suggest the existence of an ITAMi-mediated mechanism by which LAP might protect against inflammation. Sustaining LAP may open therapeutic perspectives for patients with chronic liver disease.

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Raf Kinase Inhibitory Protein Down-Expression Exacerbates Hepatic Fibrosis In Vivo and In Vitro

Cellular Physiology and Biochemistry ◽

10.1159/000452524 ◽

2016 ◽

Vol 40 (1-2) ◽

pp. 49-61 ◽

Cited By ~ 12

Author(s):

Quanfang Huang ◽

Chunhong Liang ◽

Ling Wei ◽

Jinlan Nie ◽

Shengjuan Lu ◽

...

Keyword(s):

Liver Fibrosis ◽

Liver Injury ◽

Hepatic Fibrosis ◽

Chronic Liver ◽

Chronic Liver Injury ◽

Inhibitory Protein ◽

Raf Kinase ◽

Raf Kinase Inhibitory Protein ◽

Liver Tissues

Background/Aims: Raf kinase inhibitory protein (RKIP) is closely associated with numerous tumors and participates in their development through regulating the growth, apoptosis, invasion and metastasis of tumor cells. However, the role of RKIP in chronic liver injury and particularly in liver fibrosis is still unclear. Methods: In the present study, hepatic fibrosis was induced by porcine serum (PS) in rats and primary hepatic stellate cells (HSCs) were isolated from rat livers. Moreover, locostatin was used to interfere with RKIP expression. Results: RKIP expression was significantly inhibited by locostatin in both liver tissues of rats and primary HSCs. Down-regulating RKIP expression resulted in serious liver injury, extensive accumulation of collagen, and significant increase in the levels of ALT, AST and TNF-α during liver fibrosis in rats. Moreover, down-regulating RKIP significantly promoted HSCs proliferation and colony formation in vitro. Reduced RKIP significantly increased the production of collagen and the level of α-SMA as well as the expression of MMP-1 and MMP-2 in both liver tissues and primary HSCs. Furthermore, down-regulating RKIP promoted the activation of the ERK and TLR4 signaling pathways. Conclusion: Our findings clearly indicate an inverse correlation between RKIP level and the degree of the liver injury and fibrosis. The decrease in RKIP expression may exacerbate chronic liver injury and liver fibrosis.

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