Enhanced Interstitial Collagenase (Matrix Metalloproteinase-13) Production of Kupffer Cell by Gadolinium Chloride Prevents Pig Serum-Induced Rat Liver Fibrosis

Hironaka, Koji; Sakaida, Isao; Matsumura, Yasuhiro; Kaino, Seiji; Miyamoto, Koji; Okita, Kiwamu

doi:10.1006/bbrc.1999.1910

Cited by 63 publications

(51 citation statements)

References 28 publications

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“…43,44 The current study showed that the number of CD68-and HO-1-positive cells, which are identical to activated Kupffer cells, significantly increased in group M, whereas MMP-13 mRNA expression markedly decreased. Switching the diet from MCDD to CD triggered the immediate recovery of the liver histology, accompanied by a marked increase in the expression of MMP-13 mRNA, indicating the active role of MMP-13 derived from Kupffer cells in the regression of liver fibrosis.…”

Section: Discussionsupporting

confidence: 47%

Reversibility of fibrosis, inflammation, and endoplasmic reticulum stress in the liver of rats fed a methionine–choline-deficient diet

Ogawa

Kawada

2010

Laboratory Investigation

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Fatty liver disease has become a health problem related to metabolic syndrome worldwide, although its molecular pathogenesis requires further study. It is also unclear whether advanced fibrosis of steatohepatitis will regress when diet is controlled. The aim of this study was to investigate whether the resolution of fibrosis occurs in steatohepatitis induced by a methionine-choline-deficient diet (MCDD). Manifestation of endoplasmic reticulum (ER) stress in this model was also studied. Nonalcoholic steatohepatitis with advanced fibrosis was induced in rats by feeding them an MCDD for 10 weeks. Instead of MCDD, a methionine-choline control diet (CD) was given for the last 2 weeks to the experimental group. Fibrosis and inflammation were determined by tissue staining. Protein and gene expressions were determined by immunoblotting and quantitative reverse transcription-PCR (RT-PCR), respectively. Expressions of caspase-7, caspase-12, glucose-regulated protein 78 (GRP78), and protein disulfide isomerase were evaluated to clarify the presence of ER stress. Changing the diet from MCDD to CD triggered the reduction of fat in hepatocytes, a decrease in inflammatory gene expression and oxidative stress, and regression of fibrosis accompanied by the disappearance of activated stellate cells and macrophages. Immunohistochemistry, immunoblotting, and RT-PCR analysis all indicated the occurrence of ER stress in steatohepatitis, while it recovered immediately after changing the diet from MCCD to CD. The ratio of hepatocyte proliferation/apoptotis increased significantly during the recovery stage. This simple experiment clearly shows that changing the diet from MCDD to a normal diet (CD) triggers the resolution of hepatic inflammatory and fibrotic reactions and hepatocyte apoptosis, suggesting that MCDD-induced steatohepatitis is also reversible. ER stress appears and disappears in association with the generation and regression of steatohepatitis, respectively, with fibrosis.

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Section: Discussionsupporting

confidence: 47%

Reversibility of fibrosis, inflammation, and endoplasmic reticulum stress in the liver of rats fed a methionine–choline-deficient diet

Ogawa

Kawada

2010

Laboratory Investigation

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“…Hepatic macrophages are an important source of proteases, including MMP-13. 50 Interestingly, overexpression of MMP-8 lead to partial reversal of fi brosis, providing proof of concept for a therapeutic role for overexpression of MMPs. 51 Moreover, resolution of fi brosis in CCl 4 -induced liver injury is attenuated in mice lacking MMP-13, 52 yet fi brosis is accelerated in these knockout animals with biliary fi brosis.…”

Section: Matrix Degradationmentioning

confidence: 99%

Molecular mechanism of hepatic stellate cell activation and antifibrotic therapeutic strategies

et al. 2008

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Activation of hepatic stellate cells (HSCs) is the dominant event in liver fibrosis. The early events in the organization of HSC activation have been termed initiation. Initiation encompasses rapid changes in gene expression and phenotype that render the cells responsive to cytokines and other local stimuli. Cellular responses following initiation are termed perpetuation, which encompasses those cellular events that amplify the activated phenotype through enhanced growth factor expression and responsiveness. Multiple cells and cytokines play a part in the regulation of HSC activation. HSC activation consists of discrete phenotype responses, mainly proliferation, contractility, fibrogenesis, matrix degradation, chemotaxis and retinoid loss. Currently, antifibrotic therapeutic strategies include inhibition of HSC proliferation or stimulation of HSC apoptosis, downregulation of collagen production or promotion of its degradation, administration of cytokines, and infusion of mesenchymal stem cells. In this review, we summarize the latest advances in our understanding of the mechanisms of HSC activation and possible antifibrotic therapeutic strategies.

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“…Nine members of the MMP gene family have been identified. These enzymes degrade such components of the extracellular matrix as collagen, gelatin, laminin, and proteoglycan core protein [17]. The MMPs can be grouped generally according to enzymatic substrate: collagenases, gelatinases, stromelysins and metalloelastases.…”

Section: Introductionmentioning

confidence: 99%

Matrix Metalloproteinases 2 and 9 Are Markers of Inflammation but Not of the Degree of Fibrosis in Chronic Hepatitis C

Reif

Somech²,

Brazovski³

et al. 2005

Digestion

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Background: The degree of liver fibrosis and inflammation is important in patients with chronic hepatitis C (CHC) in terms of therapy as well as prognosis. To obviate the need of liver biopsy, serum markers such as procollagen I, III and hyaluronic acid have been proposed but were found to be inaccurate. Controversy still exists regarding the role of matrix metalloproteinases (MMPs) as valid markers of liver fibrosis. Aim: To assess liver and serum MMP-2 and -9 as markers of fibrosis and inflammation in patients with CHC. Methods: Thirty-five CHC patients and 8 non-hepatitis C patients with normal liver enzymes underwent liver biopsy. Activities of inflammation and fibrosis stage were determined by the Desmet score on a scale of 0–4. Serum and liver tissue MMP-2 and -9 activities were measured by zymography using substrate impregnated gels. Results: Patient and control groups were similar in terms of age (50.8 ± 15.1 vs. 50.6 ± 15.2) and male/female ratio (18/17 vs. 4/4). In serum, MMP-9 activity was increased in patients compared to controls (308 ± 110 vs. 163.5 ± 35 , p < 0.05). In liver tissue, MMP-9 was also higher in patients than in controls (21 ± 4.5 vs. 17.1 ± 5.1, p < 0.05), whereas MMP-2 did not differ between patients and controls. Serum MMP-9 values correlated with liver histologic inflammatory grade (290.4 ± 83 in grade 2 vs. 562.1 ± 128 in grade 3, p < 0.05) but not with fibrosis stage. The highest rising in serum MMP-9 levels was observed between grade 2 to grade 3 and was superior to the rising in serum transaminase levels, indicating its advantage in assessing the progression of disease activity. No correlation between liver MMP activities and liver fibrosis or inflammation was observed. Conclusion: Serum MMPs, in particular MMP-9, can serve as markers of disease activity rather than fibrosis stage in chronic HCV patients.

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Enhanced Interstitial Collagenase (Matrix Metalloproteinase-13) Production of Kupffer Cell by Gadolinium Chloride Prevents Pig Serum-Induced Rat Liver Fibrosis

Cited by 63 publications

References 28 publications

Reversibility of fibrosis, inflammation, and endoplasmic reticulum stress in the liver of rats fed a methionine–choline-deficient diet

Reversibility of fibrosis, inflammation, and endoplasmic reticulum stress in the liver of rats fed a methionine–choline-deficient diet

Molecular mechanism of hepatic stellate cell activation and antifibrotic therapeutic strategies

Matrix Metalloproteinases 2 and 9 Are Markers of Inflammation but Not of the Degree of Fibrosis in Chronic Hepatitis C

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