• BMB Reports
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• v.55 no.4
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• pp.166-174
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• 2022

Hepatic macrophages are key immune cells associated with the broad ranges of liver diseases including steatosis, inflammation and fibrosis. Hepatic macrophages interact with other immune cells and orchestrate hepatic immune circumstances. Recently, the heterogenous populations of hepatic macrophages have been discovered termed residential Kupffer cells and monocyte-derived macrophages, and identified their distinct population dynamics during the progression of various liver diseases. Liver injury lead to Kupffer cells activation with induction of inflammatory cytokines and chemokines, which triggers recruitment of inflammatory monocyte-derived macrophages. To understand liver pathology, the functions of different subtypes of liver macrophages should be regarded with different perspectives. In this review, we summarize recent advances in the roles of hepatic macrophages under liver damages and suggest hepatic macrophages as promising therapeutic targets for treating liver diseases.

• The Korean Journal of Physiology and Pharmacology
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• v.28 no.2
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• pp.129-143
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• 2024

Sulfur dioxide (SO₂), a novel endogenous gas signaling molecule, is involved in the regulation of cardiac function. Exerting a key role in progression of hyperthyroidism-induced cardiomyopathy (HTC), myocardial fibrosis is mainly caused by myocardial apoptosis, leading to poor treatment outcomes and prognoses. This study aimed to investigate the effect of SO₂ on the hyperthyroidism-induced myocardial fibrosis and the underlying regulatory mechanisms. Elisa, Masson staining, Western-Blot, transmission electron microscope, and immunofluorescence were employed to evaluate the myocardial interstitial collagen deposition, endoplasmic reticulum stress (ERS), apoptosis, changes in endogenous SO₂, and Hippo pathways from in vitro and in vivo experiments. The study results indicated that the hyperthyroidism-induced myocardial fibrosis was accompanied by decreased cardiac function, and down-regulated ERS, apoptosis, and endogenous SO₂-producing enzyme aspartate aminotransferase (AAT)1/2 in cardiac myocytes. In contrast, exogenous SO₂ donors improved cardiac function, reduced myocardial interstitial collagen deposition, up-regulated AAT1/2, antagonized ERS and apoptosis, and inhibited excessive activation of Hippo pathway in hyperthyroid rats. In conclusion, the results herein suggested that SO₂ inhibited the overactivation of the Hippo pathway, antagonized ERS and apoptosis, and alleviated myocardial fibrosis in hyperthyroid rats. Therefore, this study was expected to identify intervention targets and new strategies for prevention and treatment of HTC.

• CELLMED
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• v.3 no.2
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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.

• The Journal of Internal Korean Medicine
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• v.45 no.4
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• pp.823-837
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• 2024

Objectives: This case report aims to present the long-term clinical progression of a patient diagnosed with alcoholic hepatitis, which subsequently advanced to liver cirrhosis and hepatocellular carcinoma over a 15-year period. The report highlights the impact of continued alcohol consumption on the progression of alcoholic liver disease and provides a clinical analysis of the course of the disease. Methods: A single patient diagnosed with alcoholic hepatitis was analyzed retrospectively. The patient was treated with both traditional Korean medicine and conventional medicine over multiple hospitalizations between 2012 and 2021. Clinical outcomes were monitored through blood chemistry, imaging studies, and Child-Pugh scores. Results: Despite consistent treatment, the patient's continued alcohol consumption accelerated the progression from alcoholic hepatitis to cirrhosis and, eventually, hepatocellular carcinoma. The patient's condition remained classified as Child-Pugh B throughout the follow-up, and he ultimately expired in 2023. Conclusion: This case emphasizes that alcohol cessation is crucial in preventing the rapid progression from alcoholic hepatitis to liver cancer. Early detection through noninvasive fibrosis tests such as FibroScan, proactive management of complications, and the use of prognostic tools such as Maddrey Discriminant function (MDF), in addition to patient education, are essential for better outcomes.

• Toxicological Research
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• v.33 no.1
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• pp.31-41
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• 2017

Side stream cigarette smoke (SSCS) is known to be as harmful and hazardous to human health as is active smoking. In this study, we investigated the relationship between the exposure to SSCS and its stimulatory and subacute effects on the progression of non-alcoholic steatohepatitis (NASH). A methionine and choline-deficient plus high fat (MCDHF) diet was administered to C57BL/6 mice for 6 weeks. During the first three weeks of MCDHF diet feeding, each diet group was exposed to SSCS (0, 20, $40{\mu}g/L$) or fresh air for 2 hrs per day and 5 days per week. Additional experiments were performed by increasing the concentration (0, 30, $60{\mu}g/L$) and exposure time (6 hours per day) of SSCS. According to histopathologic analysis and serum levels of Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST), there were no differences in hepatic fat deposition, fibrosis, apoptosis or liver damage in MCDHF-fed mice based on SSCS exposure. There were also no differences in the expression of inflammation-, oxidative stress- or fibrosis-related genes between MCDHF-fed mice with or without SSCS exposure. Therefore, it is concluded that SSCS with current exposure amounts does not have additive detrimental effects on the early stage of NASH.

• Tuberculosis and Respiratory Diseases
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• v.44 no.4
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• pp.871-888
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• 1997

Background : It is now thought that the earliest manifestation of idiopathic pulmonary fibrosis is alveolitis, that is, an accumulation of inflammatory and immune effector cells within alveolar walls and spaces. Inflammatory cells including alveolar macrophages and resident normal pulmonary tissue cells participate through the release of many variable mediators such as inflammatory growth factors and cytokines, which contribute to tissue damage and finally cause chronic pulmonary inflammation and fibrosis. This study was performed to investigate the source and distribution pattern of transforming growth factor-${\beta}_1$(TGF-${\beta}_1$), platelet derived growth factor(PDGF), basic fibroblast growth factor(bFGF), interleukin 1(IL-1), interleukin 6(IL-6), tumor necrosis factor-$\alpha$ (TNF-$\alpha$) and the role of these mediators on bleomycin(BLM)-induced pulmonary injury and fibrosis in rats. Method : Wistar rats were divided into three groups(control group, BLM treated group, BLM and vitamine E treated group). Animals were sacrificed periodically at 1, 2, 3, 4, 5, 7, 14, 21, 28 days after saline or BLM administration. The effects were compared to the results of bronchoalveolar lavage fluid analysis, light microscopic findings, immunohistochemical stains for six different mediators(TGF-${\beta}_1$, PDGF, bFGF, IL-1, IL-6 and TNF-$\alpha$) and mRNA in situ hybridization for TGF-${\beta}_1$. Results : IL-1 and IL-6 are maximally expressed at postbleomycin 1~7th day which are mainly produced by neutrophils and bronchiolar epithelium. It is thought that they induce recruitment of inflammatory cells at the injury site. The expression of IL-1 and IL-6 at the bronchiolar epithelium within 7th day is an indirect evidence of contribution of bronchiolar epithelial cells to promote and maintain the inflammatory and immune responses adjacent to the airways. TNF-$\alpha$ is mainly produced by neutrophils and bronchiolar epithelial cells during 1~5th day, alveolar macrophages during 7~28th day. At the earlier period, TNF-$\alpha$ causes recruitment of inflammatory cells at the injury site and later stimulates pulmonary fibrosis. The main secreting cells of TGF-${\beta}_1$ are alveolar macrophages and bronchiolar epithelium and the target is pulmonary fibroblasts and extracellular matrix. TGF-${\beta}_1$ and PDGF stimulate proliferation of pulmonary fibroblasts and TGF-${\beta}_1$ and bFGF incite the fibroblasts to produce extracellular matrix. The vitamine E and BLM treated group shows few positive cells(p<0.05). Conclusion : After endothelial and epithelial injury, the neutrophils and bronchiolar epithelium secrete IL-1, IL-6, TNF-$\alpha$ which induce infiltration of many neutrophils. It is thought that variable enzymes and $O_2$ radicals released by these neutrophils cause destruction of normal lung architecture and progression of pulmonary fibrosis. At the 7~28th day, TGF-${\beta}_1$, PDGF, bFGF, TNF-$\alpha$ secreted by alveolar macrophages sting pulmonary fibroblasts into proliferating with increased production of extracellular matrix and finally, they make progression of pulmonary fibrosis. TNF-$\alpha$ compares quite important with TGF-${\beta}_1$ to cause pulmonary fibrosis. Vitamine E seems to decrease the extent of BLM induced pulmonary fibrosis.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.9
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• pp.3879-3884
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• 2014

Background: In chronic hepatitis B (CHB), the presence of hepatic steatosis (HS) seems to be associated with known host and viral factors which may influence the long-term prognosis of chronic hepatitis B (CHB), probably leading to cirrhosis and hepatocellular carcinoma (HCC). Different from chronic hepatitis C (CHC), factors associated with HS in CHB are not clearly explored. Materials and Methods: 160 CHB patients were divided into two groups depending on the results of liver biopsy. Group I consisted of 71 patients with confirmed steatosis. Group II comprised 89 patients without steatosis. The groups were compared in terms of basal characteristics, body mass index (BMI), liver enzymes (ALT, AST, ALP), serum fasting blood sugar (FBS) and lipids, hepatitis B e antigen (HBeAg), viral load, and histological findings. Results: In terms of host factors, male gender, older age, BMI, high serum FBS and lipid levels were associated with HS. On the other hand, ALT levels, the HAI scores of necroinflammation and stage of fibrosis did not associate with HS. On multivariate analysis, parameters of sex, BMI, cholesterol and FBS levels were independently associated with HS. Regarding viral factors, HBeAg negativity was significantly associated with HS (81.7%, p value 0.006), but not HBV DNA level (p value 0.520). Conclusions: HS in CHB appears to be unrelated to the status of HBV replication. However, fibrosis progression in CHB is related to variable host factors. HS may be enhanced through these factors in HBV chronic patients.

• Korean Journal of Veterinary Pathology
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• v.5 no.1
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• pp.9-16
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• 2001

To investigate the effects of safflower seed supplementation diet on the hepatic injury of rats administered with carbon tetrachloride (CCI$_4$), histopathological changes were assessed following acute and chronic administration in rats. In acute cases, all rats in group fed with 10% safflower seed supplementation diet survived despite the administration of lethal doses of $CCl_4$. However, most rats in group fed with control diet died. The hepatic injuries of survived rats, in the histopathological findings, were mild compared to those of dead rats. In the chronic cases, livers of group 2 fed with control diet were more progressive in fatty changes and centrilobular necrosis than those of group 3 fed with 20%safflower seed diet. However, after six weeks, livers of group 2 and 3 showed severe necrosis and mild fibrosis at the same time. Group 5 fed with 10% safflower seed supplementation diet and water containing 0.05% phenobarbital sodium showed mild fatty changes and necrosis compared with group 4 fed with control diet and water containing 0.05% phenobarbital sodium at sixth week. At 8 to 10 wee71s after the administration of $CCl_4$, severe fibrosis. fatty changes and marked necrosis were observed in group 4, but hepatic injuries were less severe in group 5. The present results suggested that safflower seed has some protective effect in hepatic lesions and consequently delay the progression of hepatic fibrosis.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.2
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• pp.605-610
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• 2014

Chronic liver diseases, including cancer, are characterized by inflammation and elevated serum ferritin (SF). However, the causal-relationship remains unclear. This study used primary rat hepatic stellate cells (HSC) as a model to investigate effects of physiological SF concentrations (10, 100 and 1000 pM) because HSCs play a central role in the development and progression of liver fibrosis. Physiological concentrations of SF, either horse SF or human serum, induced pro-inflammatory cytokine $IL1{\beta}$, IL6 and $TNF{\alpha}$ secretion in rat activated HSCs (all p<0.05). By contrast, treatment did not alter activation marker ${\alpha}SMA$ expression. The presence of SF markedly enhanced expression of Grp78 mRNA (p<0.01). Furthermore, transient knock down of Grp78 by endotoxin EGF-SubA abolished SF-induced $IL1{\beta}$ and $TNF{\alpha}$ secretion in activated HSCs (all p<0.05). In conclusion, our results showed that at physiological concentrations SF functions as a pro-inflammatory mediator in primary rat HSCs. We also provide a molecular basis for the action of SF and identified Grp78-associated ER stress pathways as a novel potential therapeutic target for resolution of fibrosis and possible prevention of liver cancer.

• Childhood Kidney Diseases
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• v.15 no.2
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• pp.125-137
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• 2011

Purpose : Men are generally more prone to chronic renal disease and progression to end stage renal disease than women. The purpose of this study is to prove the effect of gender and sex hormone on renal fibrosis in mice with unilateral ureteral obstruction (UUO) and to elucidate the specific underlying mechanisms. Methods :We compared the expression of ${\alpha}$-smooth muscle actin (${\alpha}$-SMA) in female and male mice with complete UUO (day 7). After this, we estimated the changes of renal fibrosis in the female mice with oophorectomy and in the female mice with oophorectomy and replacement of $17{\beta}$-estradiol, respectively. Results : The level of ${\alpha}$-SMA in the female kidney with UUO was significantly lower than that in the male kidney with UUO. oophorectomy and replacement of $17{\beta}$-estradiol did not change the expression of angiotensin II type 1 (AT1) receptor in the female kidney with UUO, whereas the expression of angiotensin II type 2 (AT2) receptor was significantly more elevated in the intact female (IF) and the oophorectomized female with estrogen (OF+E) than that in the oophorectomized female (OF). The expressions of inducible nitric oxide synthase (iNOS) in the IF and OF+E mice were significantly more elevated than that in the OF mice, which was similar to the expression of AT2 receptor. Conclusion : The female gender is associated with resistance to renal fibrosis in obstructive uropathy and this gender difference may originate from the existence of $17{\beta}$-estradiol, which has an anti-fibrotic effect via upregulation of the AT2 receptor and iNOS.