Matrix metalloproteinase‐9 as a therapeutic target for the progression of fulminant liver failure with hepatic encephalopathy: A pilot study in mice

Hori, Tomohide; Üemoto, Shinji; Walden, Lindsay B.; Chen, Feng; Baine, Ann Marie T.; Hata, Toshiyuki; Kogure, Takayuki; Nguyen, Justin H.

doi:10.1111/hepr.12161

Cited by 13 publications

(13 citation statements)

References 55 publications

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“…Besides HCC, MMP-9 expression was found to be highly increased during acute liver failure (ALF) and fulminant liver failure ((FLF) defined as acute and severe impairment of liver functions) and contributed to brain extravasation and edema due to the loss of blood-brain barrier (BBB) integrity [77]. Indeed, MMP-9 depletion or inhibition improved survival, liver functions and brain injuries at the early stage (unfortunately not at the late stage 3) [78] (Table 1).…”

Section: Matrix Metalloproteinases (Mmps) and Their Role In Liver Diseasementioning

confidence: 99%

Matrix Metalloproteinases as Potential Biomarkers and Therapeutic Targets in Liver Diseases

Geervliet

Bansal

2020

Cells

118

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Chronic liver diseases, characterized by an excessive accumulation of extracellular matrix (ECM) resulting in scar tissue formation, are a growing health problem causing increasing morbidity and mortality worldwide. Currently, therapeutic options for tissue fibrosis are severely limited, and organ transplantation is the only treatment for the end-stage liver diseases. During liver damage, injured hepatocytes release proinflammatory factors resulting in the recruitment and activation of immune cells that activate quiescent hepatic stellate cells (HSCs). Upon activation, HSCs transdifferentiate into highly proliferative, migratory, contractile and ECM-producing myofibroblasts. The disrupted balance between ECM deposition and degradation leads to the formation of scar tissue referred to as fibrosis. This balance can be restored either by reducing ECM deposition (by inhibition of HSCs activation and proliferation) or enhancing ECM degradation (by increased expression of matrix metalloproteinases (MMPs)). MMPs play an important role in ECM remodeling and represent an interesting target for therapeutic drug discovery. In this review, we present the current knowledge about ECM remodeling and role of the different MMPs in liver diseases. MMP expression patterns in different stages of liver diseases have also been reviewed to determine their role as biomarkers. Finally, we highlight MMPs as promising therapeutic targets for the resolution of liver diseases.

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Section: Matrix Metalloproteinases (Mmps) and Their Role In Liver Diseasementioning

confidence: 99%

Matrix Metalloproteinases as Potential Biomarkers and Therapeutic Targets in Liver Diseases

Geervliet

Bansal

2020

Cells

118

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“…MMP-9 inhibition was shown to improve survival and liver function at the early stage [ 14 ] by inhibiting liver inflammation and damage [ 28 , 29 ]. Liver-selective MMP-9 inhibition has a proven effect in accelerating liver regeneration [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

“…As a consequence of malignant hilar biliary obstruction, acute liver failure might occur with increased MMP-9 expression and contribution to brain extravasation due to the loss of blood–brain barrier integrity. In this clinical scenario but unfortunately not at the late stage, MMP-9 inhibition could improve survival, liver function, and brain injuries [ 14 ]. MMPs expression patterns in different stages of liver diseases determine their potential role as biomarkers and a target for novel therapeutic drug discovery [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

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Effect of Percutaneous Biliary Drainage on Enzyme Activity of Serum Matrix Metalloproteinase-9 in Patients with Malignant Hilar Obstructive Hyperbilirubinemia

et al. 2023

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Background and Objectives. Cholestasis activates complex mechanisms of liver injury and as a result has an increased production of matrix metalloproteinases (MMP). Depending on the stage of liver disease, different matrix metalloproteinases expressions have been detected and could serve as indirect biomarkers as well as therapeutic targets. MMP-9 proteolytic activity has a proven role in both liver regeneration and neoplastic cell invasion in various malignancies. The purpose of this prospective cohort study was to evaluate the effect of external biliary drainage on enzyme activity of MMP-9 in the serum of patients with malignant hilar biliary obstruction. Materials and Methods. Between November 2020 and April 2021, 45 patients with malignant hilar biliary obstruction underwent percutaneous biliary drainage following determination of serum MMP-9 enzyme activity (before treatment and 4 weeks after the treatment) by gelatin zymography. Results. MMP-9 values decreased statistically significantly 4 weeks after percutaneous biliary drainage (p = 0.028) as well as the value of total bilirubin (p < 0.001), values of direct bilirubin (p < 0.001), aspartate aminotransferase (AST) (p < 0.001), alanine transaminase (ALT) (p < 0.001), and gamma-glutamyl transferase (GGT) (p < 0.001). Conclusions. In patients with malignant hilar biliary obstruction treated by external percutaneous biliary drainage for cholestasis resolution, a significant reduction in MMP-9 serum values was noted 4 weeks after the treatment.

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“…MMP-9 promotes apoptosis of HSCs [ 65 ] and is expressed in HCC [ 66 , 67 ]. In a murine model, MMP-9 was used as a therapeutic target for fulminant hepatic failure, and its inhibition led to prolonged survival by improving hepatic and brain injury at an early stage [ 68 ]. The gelatinases subgroup has three repeats of a type II fibronectin domain inserted in the catalytic domain, which allows for the binding to and processing of denatured gelatin and collagens [ 103 ].…”

Section: Molecular Mechanism Of Fibrosismentioning

confidence: 99%

Noninvasive Assessment of Liver Fibrosis: Current and Future Clinical and Molecular Perspectives

Masuzaki

Sasaki

Matsumoto

et al. 2020

IJMS

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Liver fibrosis is one of the risk factors for hepatocellular carcinoma (HCC) development. The staging of liver fibrosis can be evaluated only via a liver biopsy, which is an invasive procedure. Noninvasive methods for the diagnosis of liver fibrosis can be divided into morphological tests such as elastography and serum biochemical tests. Transient elastography is reported to have excellent performance in the diagnosis of liver fibrosis and has been accepted as a useful tool for the prediction of HCC development and other clinical outcomes. Two-dimensional shear wave elastography is a new technique and provides a real-time stiffness image. Serum fibrosis markers have been studied based on the mechanism of fibrogenesis and fibrolysis. In the healthy liver, homeostasis of the extracellular matrix is maintained directly by enzymes called matrix metalloproteinases (MMPs) and their specific inhibitors, tissue inhibitors of metalloproteinases (TIMPs). MMPs and TIMPs could be useful serum biomarkers for liver fibrosis and promising candidates for the treatment of liver fibrosis. Further studies are required to establish liver fibrosis-specific markers based on further clinical and molecular research. In this review, we summarize noninvasive fibrosis tests and molecular mechanism of liver fibrosis in current daily clinical practice.

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Matrix metalloproteinase‐9 as a therapeutic target for the progression of fulminant liver failure with hepatic encephalopathy: A pilot study in mice

Abstract: MMP-9 has therapeutic potential for FLF progression.

Cited by 13 publications

References 55 publications

Matrix Metalloproteinases as Potential Biomarkers and Therapeutic Targets in Liver Diseases

Matrix Metalloproteinases as Potential Biomarkers and Therapeutic Targets in Liver Diseases

Effect of Percutaneous Biliary Drainage on Enzyme Activity of Serum Matrix Metalloproteinase-9 in Patients with Malignant Hilar Obstructive Hyperbilirubinemia

Noninvasive Assessment of Liver Fibrosis: Current and Future Clinical and Molecular Perspectives

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