Kim, Minjeong;Hur, Sumin;Kim, Kwang H.;Cho, Yejin;Kim, Keunyoung;Kim, Ha Ryong;Nam, Ki Taek;Lim, Kyung-Min
Biomolecules & Therapeutics
/
v.30
no.2
/
pp.126-136
/
2022
Liver fibrosis is part of the wound healing process to help the liver recover from the injuries caused by various liver-damaging insults. However, liver fibrosis often progresses to life-threatening cirrhosis and hepatocellular carcinoma. To overcome the limitations of current in vivo liver fibrosis models for studying the pathophysiology of liver fibrosis and establishing effective treatment strategies, we developed a new mouse model of liver fibrosis using polyhexamethylene guanidine phosphate (PHMG-p), a humidifier sterilizer known to induce lung fibrosis in humans. Male C57/BL6 mice were intraperitoneally injected with PHMG-p (0.03% and 0.1%) twice a week for 5 weeks. Subsequently, liver tissues were examined histologically and RNA-sequencing was performed to evaluate the expression of key genes and pathways affected by PHMG-p. PHMG-p injection resulted in body weight loss of ~15% and worsening of physical condition. Necropsy revealed diffuse fibrotic lesions in the liver with no effect on the lungs. Histology, collagen staining, immunohistochemistry for smooth muscle actin and collagen, and polymerase chain reaction analysis of fibrotic genes revealed that PHMG-p induced liver fibrosis in the peri-central, peri-portal, and capsule regions. RNA-sequencing revealed that PHMG-p affected several pathways associated with human liver fibrosis, especially with upregulation of lumican and IRAK3, and downregulation of GSTp1 and GSTp2, which are closely involved in liver fibrosis pathogenesis. Collectively we demonstrated that the PHMG-p-induced liver fibrosis model can be employed to study human liver fibrosis.
Park, Eun-Jeon;Kim, Jae-Baek;Sohn, Dong-Hwan;Ko, Geon-Il
YAKHAK HOEJI
/
v.41
no.5
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pp.622-628
/
1997
Hepatic cirrhosis is a common response to chronic liver injury from many causes and is one of the most common cause of all deaths. This study was carried out to compare experimental hepatic cirrhosis in rats to understand this disease and to apply for the pharmacokinetics in disease state. Following three kinds of experimental models were induced; 1) Bile duct ligation/scission (BDL/S), 2) N, N-dimethylnitrosamine(DMN), 3) Carbon tetrachloride. The hepatic cirrhosis was characterized by examing the liver/body weight ratio, serum biochemical values, hydroxyproline content in liver and histopathological lesions in cirrhotic rat liver. The results are as follows : (1) In BDL/S, the liver was enlarged to 250% of normal liver. In contrast the liver was shrinked to 48% and 78% of the normal liver in DMN and carbon tetrachloride, respectively. (2) In carbon tetrachloride and BDL/S, the serum ALT, AST, ALP and total bilirubin levels were significantly increased to 200~300% of normal level, while ALT and total bilirubin levels were significantly increased in DMN group. (3) Hydroxyproline content in cirrhotic rat liver was significantly 200~500% higher than that of normal liver. (4) Nodular formation with fibrosis was observed in BDL/S, DMN, carbon tetrachloride induced cirrhotic rat liver.
The oxidative stress causes the cell damage and death and thereby, stimulates membrane lipid peroxidation. In this study, the correlation between the lipid peroxidation product and the parameter of liver fibrosis (cirrhosis) was investigated in cholestasis induced rats. The Sprague-Dawley rats were divided into 3 groups (sham: sham operation, BDL/S-I and BDL/S-II : bile duct ligation/scission) and were observed for 2 or 4 weeks. After observation period, the organs were weighed and the ratio of organ weight/body weight was calculated. Sera and liver tissue were used for the measurement of malondealdehyde (MDA), parameter of clinical biochemistry, total collagen content and the staining. The ratio of organ weight/body weight in BDL/S-I and BDL/S-II was significantly increased compared to sham operated group. Serological parameters (Alanine transaminase, Aspartate transaminase, Alkaline phosphatase and Total bilirubin) in BDL/S-I and BDL/S-II group were significantly higher than those in sham operated group. Concentration of MDA in BDL/S-I (261%) and BDL/S-II(790%) was significantly increased compared to MDA in sham operated group. And the content of hydroxyproline (hyp) in BDL/S-I and BDL/S-II group was significantly increased 2~4 times than in sham operated group. The good correlations between hyp in liver tissue and MDA in sera of sham operated group and all operated group were found (r=0.825). The significantly higher value of MDA, hyp and serological parameters in BDL/S-I and BDL/S-II group suggests the stimulation of lipid peroxidation and chronic liver damage. Especially the activation of lipid peroxidation and the stimulation of liver fibrosis was stronger in BDL/S-II group than in BDL/S-I group. The stronger fibrosis, portal-portal septum formation, the more massive bile duct proliferation in portal triads and stroma, and hepatocytes swelling were observed in liver tissue of and BDL/S-II group compared to BDL/S-I group. Conclusively, a good correlation between MDA as a lipid peroxidation marker and hyp as a liver fibrotic parameter could be connected with the process of liver fibrosis. Moreover, cholestasis condition may cause jaundice, activation of lipid peroxidation, and collagen accumulation in liver. Additionally, optimal observation period of bile duct obstruction for the screening of antioxidant and antifibrotic effect in rats would be four weeks.
Park, Shin-Myoung;Lee, Jang-Hoon;Kim, Young-Chul;Woo, Hong-Jung
The Journal of Internal Korean Medicine
/
v.30
no.2
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pp.270-287
/
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.
Objective: This study aimed to evaluate the role of preoperative two-dimensional (2D) shear wave elastography (SWE) in assessing the stages of liver fibrosis in patients with suspected biliary atresia (BA) and compared its diagnostic performance with those of serum fibrosis biomarkers. Materials and Methods: This study was approved by the ethical committee, and written informed parental consent was obtained. Two hundred and sixteen patients were prospectively enrolled between January 2012 and October 2018. The 2D SWE measurements of 69 patients have been previously reported. 2D SWE measurements, serum fibrosis biomarkers, including fibrotic markers and biochemical test results, and liver histology parameters were obtained. 2D SWE values, serum biomarkers including, aspartate aminotransferase to platelet ratio index (APRi), and other serum fibrotic markers were correlated with the stages of liver fibrosis by METAVIR. Receiver operating characteristic (ROC) curves and area under the ROC (AUROC) curve analyses were used. Results: The correlation coefficient of 2D SWE value in correlation with the stages of liver fibrosis was 0.789 (p < 0.001). The cut-off values of 2D SWE were calculated as 9.1 kPa for F1, 11.6 kPa for F2, 13.0 kPa for F3, and 15.7 kPa for F4. The AUROCs of 2D SWE in the determination of the stages of liver fibrosis ranged from 0.869 to 0.941. The sensitivity and negative predictive value of 2D SWE in the diagnosis of ≥ F3 was 93.4% and 96.0%, respectively. The diagnostic performance of 2D SWE was superior to that of APRi and other serum fibrotic markers in predicting severe fibrosis and cirrhosis (all p < 0.005) and other serum biomarkers. Multivariate analysis showed that the 2D SWE value was the only statistically significant parameter for predicting liver fibrosis. Conclusion: 2D SWE is a more effective non-invasive tool for predicting the stage of liver fibrosis in patients with suspected BA, compared with serum fibrosis biomarkers.
Kim, Hyun Hee;Kim, Seung Mo;Kim, Kyung Soon;Kwak, Min A;Kim, Sang Gyung;Kim, Byung Seok;Lee, Chang Hyeong
The Journal of Korean Medicine
/
v.37
no.4
/
pp.36-44
/
2016
Objectives: Granulocyte-colony-stimulating factor (G-CSF) mobilized bone marrow (BM)-derived hematopoietic stem cells could contribute to improvement of liver function. In addition, liver fibrosis can reportedly be prevented by the Rg 1 component of red ginseng. This study investigated the combined effect of G-CSF and red ginseng on decompensated liver cirrhosis. Methods: Four patients with decompensated liver cirrhosis were injected with G-CSF to proliferate BM stem cells for 4 days ($5{\mu}g/kg$ bid subcutaneously) and followed-up for 3 months. The patients also received red ginseng for 4 days (2 tablets tid per os). We analyzed Child-Pugh scores, Model for End-Stage Liver Disease (MELD) scores and cirrhotic complications. Results: All patients showed marked increases in White blood cell (WBC) and CD34+ cells in the peripheral blood, with a peak time of 4 days after G-CSF injection. Spleen size also increased after G-CSF injection, but not severely. At end of the study, 2 patients showed improvement in Child-Pugh scores, hepatic encephalopathy, and refractory ascites. During the clinical trial period, none of the 4 patients showed any other adverse events or deterioration of liver function. Conclusions: We conclude that G-CSF/red ginseng combination therapy is relatively effective in improving liver function and major complications of decompensated liver cirrhosis without adverse effects. Further clinical trials are warranted to assess the clinical effects of G-CSF for decompensated liver cirrhosis.
Seo-Won Choo;Jong-Nam Song;Cheol-Min Jeon;Jae-Bok Han
Journal of the Korean Society of Radiology
/
v.17
no.7
/
pp.1057-1065
/
2023
Non-invasive liver fibrosis diagnosis is crucial for patients with chronic liver diseases. Many patients cannot undergo liver tissue biopsy, so predicting the degree of liver fibrosis early through meaningful methods can reduce complications related to chronic liver diseases, such as liver cell carcinoma and cirrhosis. This study compared and analyzed the quantitative measurement of liver fibrosis using shear wave elastography in conjunction with liver ultrasound findings and their associations with serum biomarkers (p<0.05). The results showed that the shear wave elastography measurement in the normal group was 4.55 ± 0.69 kPa, while the abnormal contrast group with echogenic patterns had a measurement of 8.27 ± 1.83 kPa. The hepatitis B carrier group exhibited higher shear wave elastography measurements, and among serum biomarkers, AST, ALT, GGT, and PT showed statistically significant positive correlations with fibrosis severity according to SWE categories (p<0.05), while ALP and TB did not demonstrate statistically significant differences (p=0.163, p=0.567). Conversely, Albumin and PLT showed significant negative correlations (p<0.05). Clinically, utilizing shear wave elastography measurements through liver ultrasound in the tracking and repeat testing of liver fibrosis in chronic hepatitis B patients without cirrhosis can assist in achieving more objective diagnoses among healthcare providers.
Kim, Ki-Young;Oh, Se-Mi;Kim, Jin-Sook;Somasundaram, Rajan;Ruehl, Martin;Matthes, Burkhard
Proceedings of the PSK Conference
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2003.10b
/
pp.86.2-87
/
2003
Introduction: Liver fibrosis is defined unbalance of collagen metabolism, especially a stimulation of collagen synthesis and inhibition of collagen degradation, and antifibrotic effect is delaying or inhibition of new collagen synthesis and deposition in liver tissue. In this study, we investigated the antifibrotic and antioxidative effect of Solanum lycopersicum (SL) in liver fibrosis induced rats. Methods: : Rats were randomly divided in three groups (normal, CCl$_4$ and CCl$_4$-SL group) and were received 0.6 ml mixture of CCl$_4$ and olived oil (1:1 v/v) 3 times/week for 4 weeks except of the normal group. (omitted)
Park, Eun-Jeon;Kim, Ki-Young;Kim, Jae-Baek;Kim, Soo-Woong;Lee, Seung-Yong;Sohn, Dong-Hwan
YAKHAK HOEJI
/
v.38
no.3
/
pp.338-344
/
1994
This study was carried out to investigate the antifibrotic effects of polysaccharides extracted from Garnoderma lucidum. The biliary cirrhosis was induced by bile duct ligation/scission (BDL/S) in rats. BDL/S rats were dosed 5 mg/rat/day orally for 4 weeks after the operation. Antifibrotic effects were evaluated by serum biochemical values, serum procollagen type III peptide (PIIINP) levels, liver hydroxyproline contents, and light microscopical histology. The results obtained were as follows; 1) PIIINP levels in sera of treated BDL/S group were lowered to 50% of those of untreated BDL/S group. 2) Hydroxyproline contents in the liver of treated BDL/S group were also reduced to 83% of those of untreated BDL/S rats. 3) The hepatic damage such as hepatocellular necrosis, inflammation, bile duct proliferation and fibrosis was less severe in the livers of treated rats. These results suggest polysaccharides extracted from Garnoderma lucidum to be a promising agent for the inhibition of hepatic cirrhosis(fibrosis).
Antifibrotic drugs could be delayed or inhibited massive collagen deposition in liver tissue or inhibited collagen synthesis. we investigated antifibrotic effects by several herbs(Schisnadra chinensis, Ganoderma japonicum, Sedum sarmentosum, Alisma canaliculatum, Plantago asiatica) extract with observations of collagen accumulation in liver tissue and collagen synthesis in sera. Rats were used for experimental animal that were devided 3 groups(sham control, BDL/S, BDL/S-ER). Rats were operated for inducing liver fibrosis(cirrhosis) by bile duct obstruction. Several herbs were prepared by water extraction and were applicated p. o. $3ml/day$ during 4 weeks. After observation period, rats were sacrificed and liver tissue and sera were collected. In result, the mortality of rats was 35% in BDL/S group and 20% in BDL/S-ER The color of bile juice in BDL/S-ER was bright yellow and murky yellow in BDL/S group. The significantly lower weight of liver($16.21g{\pm}5.3,\;20.58{\pm}2.4$) and spleen($1.96g{\pm}0.96,\;3.93{\pm}0.21$) were shown in BDL/S-ER than that of BDL/S(p<0.05) group. The value of collagen in liver tissue(25.7%) in BDL/S-ER was observed significantly lower than that of BDL/S group (Tab. 2). AST. ALT, ALP, t-bilirubin, BUN levels were low in BDL/S-ER as compared with those of BDL/S group, but the significance was not proven. The trichrome stained liver tissue in BDL/S-ER group was observed mild bile duct proliferation and fibrosis compared with BDL/S group. In conclusion, natural products inhibited new collagen synthesis and delayed massive collagen deposition in liver tissue, so that they have noticeable antifibrotic effects in experimental liver fibrosis(cirrhosis).
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