• 대한임상검사과학회지
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• 제36권2호
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• pp.163-172
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• 2004

Mast cells (MCs) have been implicated in the pathogenesis of tissue fibrosis. However, the role of MC in the development of liver fibrosis has not been fully elucidated. Stem cell factor (SCF) is known to recruit MCs to the liver following injury as it induces mast cell proliferation, survival and differentiation from resident tissue precursors. This study examines the interaction between activated hepatic stellate cells (HSCs) and MCs in rat fibrotic liver, and SCF production by HSCs during culture in vitro. Rats were studied 4, 7, 14 and 21 days after bile duct ligation (BDL). Fibrogenesis was assessed by a measurement of collagen stained with sirius red F3B. Activated HSCs and MCs were identified by ${\alpha}$-smooth muscle actin (${\alpha}-SMA$) immunohistochemical and alcian blue staining and measured by a computerized image analysis system. SCF production was determined in rat HSC cultures using Western blotting. Mild fibrotic changes were noted in BDL rat livers as early as 4 days after induction of cholestasis. Significant expansion and organization of fibrous tissue has occurred in day 14 BDL rats which progressed to bridging fibrosis by day 21. In BDL rats, both a large number of activated HSCs and MCs were detected in portal tracts and fibrous septa. Both area of activated HSCs infiltration and density of MCs were significantly higher in all BDL group compared with Shams. In BDL rats, both areas of activated HSCs infiltration and density of MCs were no significant difference between day 4 and 7 and were significantly higher in day 14. However, the areas of activated HSCs infiltration were significantly lesser in day 21 and the densities of MCs were significantly higher in day 21 compared with day14 BDL. In BDL rats, both areas of activated HSCs infiltration and density of MCs were highly correlated with areas of fibrosis. Western blotting showed that SCF protein was consistently produced in activated HSCs by culture on plastic and freshly isolated HSCs expressed relatively little 30kD SCF compared to late primary culture activated HSCs (day 14) and passaged HSCs. These results suggest that HSCs activated in vitro produce SCF, and may play an important role in recruiting mast cells to the liver during injury and fibrosis.

• Pediatric Gastroenterology, Hepatology & Nutrition
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• 제23권4호
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• pp.346-355
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• 2020

Purpose: Peroxisome proliferator-activated receptor gamma (PPAR-γ) has a key role in hepatic fibrogenesis by virtue of its effect on the hepatic stellate cells (HSCs). Although many studies have shown that PPAR-γ agonists inhibit liver fibrosis, the mechanism remains largely unclear, especially regarding the cross-talk between PPAR-γ and other potent fibrogenic factors. Methods: This experimental study involved 25 male Wistar rats. Twenty rats were subjected to bile duct ligation (BDL) to induce liver fibrosis, further divided into an untreated group (BDL; n=10) and a group treated with the PPAR-γ agonist thiazolidinedione (TZD), at 14 days post-operation (BDL+TZD; n=10). The remaining 5 rats had a sham operation (sham; n=5). The effect of PPAR-γ agonist on liver fibrosis was evaluated by histopathology, protein immunohistochemistry, and mRNA expression quantitative polymerase chain reaction. Results: Histology and immunostaining showed markedly reduced collagen deposition, bile duct proliferation, and HSCs in the BDL+TZD group compared to those in the BDL group (p<0.001). Similarly, significantly lower mRNA expression of collagen α-1(I), matrix metalloproteinase-2, platelet-derived growth factor (PDGF)-B chain, and connective tissue growth factor (CTGF) were evident in the BDL+TZD group compared to those in the BDL group (p=0.0002, p<0.035, p<0.0001, and p=0.0123 respectively). Moreover, expression of the transforming growth factor beta1 (TGF-β1) was also downregulated in the BDL+TZD group (p=0.0087). Conclusion: The PPAR-γ agonist inhibits HSC activation in vivo and attenuates liver fibrosis through several fibrogenic pathways. Potent fibrogenic factors such as PDGF, CTGF, and TGF-β1 were downregulated by the PPAR-γ agonist. Targeting PPAR-γ activity may be a potential strategy to control liver fibrosis.

• 약학회지
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• 제40권5호
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• pp.550-557
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• 1996

One of therapeutics in liver disease (morbus wilson) is D-penicillamin (D-pen: D-3-mercapto-valin). Especially the cross-linking of collagen molecules could be inhibited by D-pe n in extracellular space. In this study we investigated the antifibrotic effects of D-pen in rats that were induced the liver fibrosis by bile duct ligation and scission (BDL/S). Rats were treated for 4 weeks with D-pen after BDL/S operation or sham operation. The balance between fibrogenesis-marker (PNIIIP) and the fibrolysis-maker (PNIVP) were observed in sera by RIA (radioimmunoassay), and the parameter of collagen deposition in liver tissue (hydroxyproline: HYP) was measured by colorimetry. The weight of liver in BDL/S operated group was increased significantly in compared with sham operation group (15.2g${\pm}$1.1, vs 11.9g${\pm}$3.9: p<0.005, p<0.05). The rats group treated by D-pen showed the lower level of PNIIIP (6.7ng/ml${\pm}$1.5, vs 9.5ng/ml${\pm}$2.8) and the higher value of PIVCP (14.0ng/ml${\pm}$1.9, vs 7.9ng/ml${\pm}$1.5) in sera that compared to untreated rats. The content of HYP was decreased by 141% in BDL/S with D-pen treated group than that of it in BDL/S group. No correlation was revealed between collagen parameters in sera and HYP in liver tissue of BDL/S operated and D-pen treated rats. The group treated with D-pen showed the lower value of clinical biochemistry parameters (GOT: glutamate oxalacetate transaminase, Total-Bilirubin) in compared with only BDL/S operated rats, but the value of GPT (glutamate pyruvate transaminase) and Alkaline phosphatase in two BDL/S groups was nearly same. In the histological finding, we observed mild bile duct proliferation, weak inflammation and fibrosis in BDL/S with D-pen treated group, but BDL/S operated group showed the formation of septum (island of hepatocytes), massive bile duct proliferation. This result represents that the BDL/S operation induces liver fibrosis (cirrhosis) in 4 weeks, and D-pen inhibits the synthesis of collagen weakly and stimulates the degradation of collagen in the extracellular space. We conclude that the monitoring of PNIIIP, PIVCP in sera is useful parameter for screening of antifibrotic effect, and D-pen delay the liver fibrosis.

• BMB Reports
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• 제55권10호
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• pp.481-487
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• 2022

Over the past few years, hydrogen sulfide (H₂S) has been shown to exert several biological functions in mammalian. The endogenous production of H₂S is mainly mediated by cystathione β-synthase, cystathione γ-lyase and 3-mercaptopyruvate sulfur transferase. These enzymes are broadly expressed in liver tissue and regulates liver function by working on a variety of molecular targets. As an important regulator of liver function, H₂S is critically involved in the pathogenesis of various liver diseases, such as non-alcoholic steatohepatitis and liver cancer. Targeting H₂S-generating enzymes may be a therapeutic strategy for controlling liver diseases. This review described the function of H₂S in liver disease and summarized recent characterized role of H₂S in several cellular process of the liver.

• 동의생리병리학회지
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• 제17권1호
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• pp.118-122
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• 2003

Oxidative stress and its consequent lipid peroxidation exert harmful effects, which have been currently involved in the generation of carbon tetrachloride (CCl₄)-induced fibrosis(cirrhosis). In this study, it was investigated whether dried extract of 田螺(Concha Cipangopaludinae; CC) has liver functional improvement, antioxidative and antifibrotic effect in rats those were induced liver fibrosis by CCl₄ administration. The female Sprague-Dawley rats were divided into 3 groups(Normal, AC, AC-CC) and were observed in 6 weeks. Except for normal group, liver fibrosis(cirrhosis) in rats were developed by CCl₄ administration(0.8 ㎖/rat/week). And the rats were treated with prepared CC(p. o. 2 ㎖/day/rat). At the time of sacrifice, the liver, kidney and spleen were weighed and the ratio of organ weight/body weight was calculated. The MDA, hyp and biochemical parameters(AST, ALT, ALP, t-bili) were measured in sera and liver tissue of rats. The strong yellow color of urine was observed in all CCl₄-treated group compared with normal group, but jaundice didn't appear in CCl₄-treated group. The mortality of CCl₄-treated group is very low(<13%) during 6 weeks of observation time. The ratio of liver/body as well as the weight of liver in CCl₄-treated rats significantly increased compared with that in normal group(p<0.001). The level of clinical parameters in sera of all liver fibrosis(cirrhosis) developed rats were significantly higher than that of normal group(p<0.001-0.05). Especially the value of BUN, ALP, t-bilirubin in AC-CC group showed 20.9%, 19.6%, 47.9% lower than that in AC group. The content of hyp in CCl₄-treated rats was significantly higher than normal group(p<0.001～<0.05), and showed 12.2% lower value in the AC-CC group than AC group(p<0.05). The production of lipid peroxidation(MDA) in sera and liver tissue significantly increased under the fibrotic(cirrhotic) condition(p<0.001～<0.05). Especially the MDA value of AC-CC group in sera significantly 46.5% decreased compared with that of AC group(p<0.05), and the MDA value of AC-CC in liver tissue showed 21.4% lower than that of AC group. Concha Cipangopaludinae can be improved hepatic function, and maybe have effect of liver protection, antioxidation and antifibrosis.

• 대한한방내과학회지
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• 제30권2호
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• pp.270-287
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• 2009

Objective : Yinjinchunggan-tang(YJCGT) is reported previously as having theraputic effects on hepatitis such as anti-implammatory, anti-apoptotic, anti-viral(HBV), etc. Though this prescription is not studied on its anti-fibrogenic effect, it is still expected to have the effect in the liver. Thus, this study was performed to investigate the anti-fibrogenic effect of YJCGT on thioacetamide(TAA)-induced liver fibrosis in rats. Method: Rat liver fibrosis was induced by intraperitoneal TAA injection(150mg/kg) 3 times a week for 5 weeks. After the YJCGT (YJCGT 1g/kg, YJCGT 2g/kg)-treatment, body weight, liver and spleen weights, liver function test, the complete blood count and the portal pressure were studied. In addition, gene expressions of ASMA, procollagen type Ia2, MMP2, TIMP1 and TIMP2, all of which are known to be associated with liver fibrosis, were analyzed by RT-PCR. After YJCGT (YJCGT 1g/kg, YJCGT 2g/kg) treatment, percentages of collagen in TAA-induced rat liver tissue were measured by image analyzer. Results : The body weight of the normal group increased more than that of the control and YJCGT-treated groups. The AST level of the YJCGT lg/kg-treated group significantly decreased compared to that of the control. The ALT and the GGT levels of the YJCGT 2g/kg-treated group significantly increased compared to those of the control. In the YJCGT-treated groups. WBC, RBC and Hgb elevated by TAA injection decreased but platelet count increased. In the YJCGT lg/kg-treated group, the portal pressure elevated by TAA injection significantly decreased. The significant decreases in the gene expressions of procollagen type Ia2, MMP2 and TIMP2 were observed in the YJCGT-treated groups. In histological findings. TAA injections caused severe liver fibrosis, but the YJCGT treatment significantly reduced the amounts of hepatic collagens. Conclusions: These results suggest that YJCGT has beneficial effects on the treatment of patients with liver cirrhosis as well as chronic hepatitis. Further study should be done to decide the optimal concentration of the YJCGT for the treatment of liver cirrhosis.

• BMB Reports
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• 제53권6호
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• pp.317-322
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• 2020

Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases. NAFLD can further progress to irreversible liver failure such as non-alcoholic steatohepatitis (NASH) fibrosis and cirrhosis. However, specific regulator of NASH-fibrosis has yet to be established. Here, we found that glutathione peroxidase 7 (GPx7) was markedly expressed in NASH fibrosis. Although GPx7 is an antioxidant enzyme protecting other organs, whether GPx7 plays a role in NASH fibrosis has yet to be studied. We found that knockdown of GPx7 in transforming growth factor-β (TGF-β) and free fatty acids (FFA)-treated LX-2 cells elevated the expression of pro-fibrotic and pro-inflammatory genes and collagen synthesis. Consistently, GPx7 overexpression in LX-2 cells led to the suppression of ROS production and reduced the expression of pro-fibrotic and pro-inflammatory genes. Further, NASH fibrosis induced by choline-deficient amino acid defined, high fat diet (CDAHFD) feeding was significantly accelerated by knockdown of GPx7, as evidenced by up-regulated liver fibrosis and inflammation compared with CDAHFD control mice. Collectively, these results suggest that GPx7 might be a novel therapeutic target to prevent the progression and development of NAFLD.

• 대한간학회지
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• 제24권4호
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• pp.392-401
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• 2018

Background/Aims: Leptin is associated with metabolic disorders, which predispose one to non-alcoholic fatty liver disease (NAFLD). The role of leptin in NAFLD pathogenesis is not fully understood. We aim to investigate the association between serum leptin level and severity of NAFLD using U.S. nationally representative data. Methods: Data were obtained from the United States Third National Health and Nutrition Examination Survey. NAFLD was defined by ultrasound detection and severity of hepatic steatosis in the absence of other liver diseases. The severity of hepatic fibrosis was determined by NAFLD fibrosis score (NFS). We used multivariate survey-weighted generalized logistic regression to evaluate the association between leptin level and the degree of NAFLD. We also performed subgroup analyses by body mass index (lean vs. classic NAFLD). Results: Among 4,571 people, 1,610 (35%) had NAFLD. By ultrasound findings, there were 621 people with mild, 664 with moderate, and 325 with severe steatosis. There were 885 people with low NFS (<-1.455, no significant fibrosis), 596 with intermediate NFS, and 129 with high NFS (>0.676, advanced fibrosis). Leptin levels for normal, mild, moderate and severe steatosis were $10.7{\pm}0.3ng/mL$, $12.1{\pm}0.7ng/mL$, $15.6{\pm}0.8ng/mL$, $16{\pm}1.0ng/mL$, respectively (trend P-value<0.001). Leptin levels for low, intermediate, and high NFS were $11.8{\pm}0.5ng/mL$, $15.6{\pm}0.8ng/mL$, $28.5{\pm}3.5ng/mL$, respectively (trend P-value<0.001). This association remained significant even after adjusting for known demographic and metabolic risk factors. In the subgroup analysis, this association was only prominent in classic NAFLD, but not in lean NAFLD. Conclusions: Serum leptin level is associated with the severity of NAFLD, especially in classic NAFLD patients.

• 대한약학회:학술대회논문집
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• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.1
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• pp.176.1-176.1
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• 2003

The protective effects on hepatic fibrosis of an aqueous extract from the roots of Platycodon grandiflorum A. DC (Campanulaceae), Changkil (CK), in hepatic stellate cell line, CFSC-2G. The increased deposition of extracellular matrix by hepatic stellate cells following liver injury in a process known as activation is considered a key mechanism for increased collagen content of liver during the development of liver fibrosis. (omitted)

• 셀메드
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• 제3권2호
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• pp.15.1-15.5
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• 2013

Previous reports showed that Compound Astragalus and Salvia miltiorrhiza extract (CASE), which was mainly composed of astragalosides, astragalus polysaccharide and salvianolic acids, inhibited hepatic fibrosis by mediating transforming growth factor-${\beta}$ (TGF-${\beta}$)/Smad signaling. Our aim was to examine the effects of CASE on D-galactosamine (D-GalN) treated liver injury in mice and carbon tetrachloride ($CCl_4$)-induced liver fibrosis in rats. CASE was administered to mice with D-GalN-induced liver injury and to rats with $CCl_4$-induced liver fibrosis, respectively. Liver injury was routinely evaluated by relative liver weight, serum levels of ALT, AST, hyaluronic acid (HA), hepatic malondialdehyde (MDA) content, superoxide dismutase (SOD) activity, hydroxyproline (HYP) and histopathologic changes. Treatment of mice with CASE (60, 120, and 240 mg/kg, ig) significantly lowered ALT, relative liver weight, and MDA levels when compared with D-GalN treated mice. CASE (120, 240 mg/kg) significantly lowered ALT, AST, HA, HYP, and MDA levels against $CCl_4$ treated rats. Decreased SOD level was reversed with CASE treatment. Upon histopathological examination, CASE treatment had significantly inhibitory effect on the progression of hepatic fibrosis in rats. These results indicate that CASE might be effective in treatment and prevention of acute and chronic hepatic injury due to its antioxidant activity.