Inhibition of hepatic stellate cell activation following Yinchenhao decoction administration to dimethylnitrosamine‐treated rats

Liu, Cheng; Sun, Mingyu; Yan, Xiaofeng; Han, Lin; Zhang, Yan; Liu, Chenghai; El-Nezami, Hani; Liu, Ping

doi:10.1111/j.1872-034x.2008.00346.x

Cited by 18 publications

(18 citation statements)

References 45 publications

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“…25,28 It is interesting to observe that the a-SMA-positive HSCs in the portal areas and fibrotic septa were free of TUNEL staining. Consistent with our earlier report, 20 this finding is not unexpected and we believe that the following factors might make a contribution to this result. First of all, in the livers treated with 2-week DMN, there was already a peak in the level of apoptotic cells, whereas HSC activation, shown as a-SMA-positive cells, has just begun to be activated.…”

Section: Discussionsupporting

confidence: 94%

“…This result was consistent with our earlier reports: a-SMA-positive-HSCs did not co-localize with TUNEL-positive cells in DMN-induced liver fibrosis. 20 Co-localization of TUNEL and a-SMA was also scarcely observed in 6-or 9-week CCL4 rats (Supplementary Figure 5). TUNEL and CD68-double-positive apoptotic KCs (Figure 5a and e) laid closely adjacent to a-SMA þ HSCs (Figure 5d and h).…”

Section: Fas-mediated Cd68-positive Kc Apoptosismentioning

confidence: 95%

“…We recently showed that a-smooth muscle actin (a-SMA)-positive HSC apoptosis was not frequently observed in DMN-induced liver fibrosis. 20 Here, we seek to ascertain the functional status of KCs and show the pathophysiological involvements of KCs in DMN and carbon tetrachloride (CCL4)-induced liver fibrosis in vivo through a detailed confocal laser microscopy study. We discovered evidences that a portion of KCs might undergo apoptosis in DMN-and CCL4-treated liver and that KCs might activate HSCs by secreting TNF-a and/or directly interacting with HSCs.…”

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confidence: 99%

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Kupffer cells are associated with apoptosis, inflammation and fibrotic effects in hepatic fibrosis in rats

Liu

Tao

Sun

et al. 2010

Laboratory Investigation

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130

103

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Hepatocellular apoptosis, hepatic inflammation, and fibrosis are prominent features in chronic liver diseases. However, the linkage among these processes remains mechanistically unclear. In this study, we examined the apoptosis and activation of Kupffer cells (KCs) as well as their pathophysiological involvement in liver fibrosis process. Hepatic fibrosis was induced in rats by dimethylnitrosamine (DMN) or carbon tetrachloride (CCl4) treatment. KCs were isolated from normal rats and incubated with lipopolysaccharide (LPS) or from fibrotic rats. The KCs were stained immunohistochemically with anti-CD68 antibody, a biomarker for KC. The level of expression of CD68 was analyzed by western blot and real-time PCR methods. The apoptosis and pathophysiological involvement of KCs in the formation of liver fibrosis were studied using confocal microscopy. The mRNA and protein expression of CD68 were significantly increased in DMNand CCL4-treated rats. Confocal microscopy analysis showed that CD68-positive KCs, but not a-smooth muscle actin (SMA)-positive cells, underwent apoptosis in the liver of DMN-and CCL4-treated rats. It was also revealed that the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and CD68-double-positive apoptotic KCs located in the portal or fibrotic septa area were situated next to hepatic stellate cells (HSCs). Tumor necrosis factor-a (TNF-a) and KC co-localized in the liver in the neighbor of HSCs. The double a-SMA-and collagen type I-positive cells predominantly existed in fibrotic septa, and those cells were co-localized clearly with CD68-positive cells. Interestingly, some CD68 and Col (1) double positive, but completely negative for a-SMA, were found in the portal areas and hepatic sinusoids; this phenomenon was also validated in primary isolated KCs after 6 h LPS exposure or fibrotic rats in vitro. These results show that KCs are associated with hepatocellular apoptosis, inflammation, and fibrosis process in a liver fibrosis models.

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Section: Discussionsupporting

confidence: 94%

Section: Fas-mediated Cd68-positive Kc Apoptosismentioning

confidence: 95%

mentioning

confidence: 99%

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Kupffer cells are associated with apoptosis, inflammation and fibrotic effects in hepatic fibrosis in rats

Liu

Tao

Sun

et al. 2010

Laboratory Investigation

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130

103

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“…It has also been reported that YHCT can alleviate obstructive biliary cirrhosis induced by bile duct ligation in rats via inhibiting biliary epithelial cell proliferation and activation 31 . Our previous study also demonstrated that YHCT administration alleviated liver fibrosis via inhibiting hepatic stellate cell (HSC) activation in dimethylnitrosamine-treated rats 32, 33 . Studies by Takahashi et al .…”

Section: Discussionmentioning

confidence: 88%

Herbal medicine Yinchenhaotang protects against α-naphthylisothiocyanate-induced cholestasis in rats

Yan

Xie

Liang

et al. 2017

Sci Rep

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Cholestasis is a clinical disorder defined as an impairment of bile flow, and that leads to toxic bile acid (BA) accumulation in hepatocytes. Here, we investigated the hepatoprotective effect of Yinchenhaotang (YCHT), a well-known formulae for the treatment of jaundice and liver disorders, against the cholestasis using the α-naphthylisothiocyanate (ANIT)-induced cholestasis in male Wistar rats. ANIT feeding induced significant cholestasis with substantially increased intrahepatic retention of hydrophobic BAs. The dynamic changes of serum and liver BAs indicated that YCHT was able to attenuate ANIT-induced BA perturbation, which is consistent with the histopathological findings that YCHT significantly decreased the liver damage. YCHT treatment substantially reduced serum alanine aminotransferase (ALT), alkaline phosphatase (AST), total bilirubin (TBIL) and direct bilirubin (DBIL) with minimal bile duct damage in the ANIT treated rats. Elevated mRNA expression of liver IL-6, IL-17A, IL-17F, TGF-β1, α-SMA, TGR5, NTCP, OATP1a1, and ileum ASBT and decreased liver IL-10, FXR, CAR, VDR, BSEP, MRP2, MRP3, MRP4 was also observed in ANIT-induced cholestasis but were attenuated or normalized by YCHT. Our results demonstrated that the BA profiles were significantly altered with ANIT intervention and YCHT possesses the hepatoprotective potential against cholestatic liver injury induced by hepatotoxin such as ANIT.

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“…Macrophages are known to play an important role in liver fibrosis and cirrhosis (Heinrichs et al, 2011;Zimmermann et al, 2011;Heymann et al, 2012;Ramachandran et al, 2012), which is a central component of the final, common pathway leading to HSC activation and ECM deposition (Liu et al, 2008(Liu et al, , 2010Chiu et al, 2014). However, the macrophage in kidneys with cirrhosis has not been well studied.…”

Section: Discussionmentioning

confidence: 99%

Xiayuxue decoction reduces renal injury by promoting macrophage apoptosis in hepatic cirrhotic rats

et al. 2015

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ABSTRACT. Renal pathological changes in cirrhotic rat have not been extensively reported. The aim of this study was to investigate whether Xiayuxue decoction (XYXD) could attenuate renal injury induced by bile duct ligation (BDL), with special focus on the mechanisms promoting renal macrophage apoptosis. The rats were treated with BDL for 5 weeks and administered 0.36 g/kg XYXD intragastrically from day 1 of initiating BDL. Renal tissue was monitored by hematoxylin-eosin and Sirius red staining. Macrophage infiltration and proinflammatory cytokines such as tumor necrosis factor and chemokine ligand 2 were detected by quantitative polymerase chain reaction. Macrophage apoptosis was detected by double immunofluorescence staining. Blood urea nitrogen, creatinine, and glomerulus diameter increased significantly after a 5-week BDL treatment in XYXD (BDL-XYXD) rats. CD68 and pro-inflammatory cytokine (2015) mRNA increased in the kidneys of control (BDL-water) rats. Fluorescence microscopy analysis showed that XYXD promoted apoptosis in renal CD68+ macrophages. Collogen1 (Col 1), pro-fibrogenic cytokines, and α-smooth muscle actin in kidneys of BDL-water rats increased significantly compared to the sham group. XYXD inhibited Col 1 and pro-fibrotic factors in BDL-XYXD rats. Our results demonstrated that XYXD significantly reduced renal injury by, at least in part, promoting macrophage apoptosis in rats with damaged renal histopathology due to BDL-induced cirrhosis.

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Inhibition of hepatic stellate cell activation following Yinchenhao decoction administration to dimethylnitrosamine‐treated rats

Abstract: Yinchenhao administration attenuates liver fibrosis at least in part by inhibiting HSC activation directly, rather than promoting cell apoptosis of activated HSC, and the suppressive activation of Kupffer cells.

Cited by 18 publications

References 45 publications

Kupffer cells are associated with apoptosis, inflammation and fibrotic effects in hepatic fibrosis in rats

Kupffer cells are associated with apoptosis, inflammation and fibrotic effects in hepatic fibrosis in rats

Herbal medicine Yinchenhaotang protects against α-naphthylisothiocyanate-induced cholestasis in rats

Xiayuxue decoction reduces renal injury by promoting macrophage apoptosis in hepatic cirrhotic rats

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