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Effects of Melittin Treatment in Cholangitis and Biliary Fibrosis in a Model of Xenobiotic-Induced Cholestasis in Mice.

Kim KH, Sung HJ, Lee WR, An HJ, Kim JY, Pak SC, Han SM, Park KK - Toxins (Basel) (2015)

Bottom Line: In previous studies, melittin was known for attenuation of hepatic injury, inflammation and hepatic fibrosis.DDC feeding led to increased serum markers of hepatic injury, ductular reaction, induction of pro-inflammatory cytokines and biliary fibrosis.Further studies on the anti-inflammatory capacity of melittin are warranted for targeted therapy in cholangiopathy.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, College of Medicine, Catholic University of Daegu, 3056-6, Daemyung-4-Dong, Nam-gu, Daegu 705-718, Korea. khkim1@cu.ac.kr.

ABSTRACT
Cholangiopathy is a chronic immune-mediated disease of the liver, which is characterized by cholangitis, ductular reaction and biliary-type hepatic fibrosis. There is no proven medical therapy that changes the course of the disease. In previous studies, melittin was known for attenuation of hepatic injury, inflammation and hepatic fibrosis. This study investigated whether melittin provides inhibition on cholangitis and biliary fibrosis in vivo. Feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to mice is a well-established animal model to study cholangitis and biliary fibrosis. To investigate the effects of melittin on cholangiopathy, mice were fed with a 0.1% DDC-containing diet with or without melittin treatment for four weeks. Liver morphology, serum markers of liver injury, cholestasis markers for inflammation of liver, the degree of ductular reaction and the degree of liver fibrosis were compared between with or without melittin treatment DDC-fed mice. DDC feeding led to increased serum markers of hepatic injury, ductular reaction, induction of pro-inflammatory cytokines and biliary fibrosis. Interestingly, melittin treatment attenuated hepatic function markers, ductular reaction, the reactive phenotype of cholangiocytes and cholangitis and biliary fibrosis. Our data suggest that melittin treatment can be protective against chronic cholestatic disease in DDC-fed mice. Further studies on the anti-inflammatory capacity of melittin are warranted for targeted therapy in cholangiopathy.

No MeSH data available.


Related in: MedlinePlus

Melittin inhibits fibrotic changes in DDC-fed mice. Immunohistochemical staining findings demonstrated that melittin effectively suppresses the expression of FSP-1. Representative immunohistochemical images from each study group (five mice per group) (A) NC, normal control group; (B) Mel, melittin (0.1 mg/kg)-treated group with normal diet; (C) DDC, 0.1% DDC-supplemented diet group; (D) DDC + Mel, melittin (0.1 mg/kg)-treated group with 0.1% DDC-supplemented diet; magnification × 200; (E) morphometric assessment of the trichrome staining positive areas. Results are expressed as the mean ± SE of three independent determinations. *p < 0.05 compared to the NC group. †p < 0.05 compared to the Mel group. ‡p < 0.05 compared to the DDC group.
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toxins-07-03372-f007: Melittin inhibits fibrotic changes in DDC-fed mice. Immunohistochemical staining findings demonstrated that melittin effectively suppresses the expression of FSP-1. Representative immunohistochemical images from each study group (five mice per group) (A) NC, normal control group; (B) Mel, melittin (0.1 mg/kg)-treated group with normal diet; (C) DDC, 0.1% DDC-supplemented diet group; (D) DDC + Mel, melittin (0.1 mg/kg)-treated group with 0.1% DDC-supplemented diet; magnification × 200; (E) morphometric assessment of the trichrome staining positive areas. Results are expressed as the mean ± SE of three independent determinations. *p < 0.05 compared to the NC group. †p < 0.05 compared to the Mel group. ‡p < 0.05 compared to the DDC group.

Mentions: Chronic exposure to injuries in cholangitis becomes a progressive course of cholestatic liver with inflammation and fibrosis of bile ducts. Much attention has been focused on the central role of TGF-β1 upregulation as a prototypical fibrogenic cytokine in liver fibrosis [17]. Western blotting results showed that the expression of TGF-β1 was significantly increased in DDC mice, whereas melittin treatment markedly decreased the expression of TGF-β1 in DDC + Mel livers (Figure 6). The expressions of TGF-β1-regulated ECM protein, fibronectin and vimentin were increased in DDC-fed mice. Treatment with melittin effectively abrogated this increase in the DDC + Mel group. During tissue remodelling in liver fibrosis, FSP-1 is considered a marker of fibroblasts in fibrotic liver. DDC feeding significantly increased the number of cells positive for FSP-1 (Figure 7). However, melittin treatment resulted in a reduction in the FSP-1-positive cells in DDC + Mel livers. Along with the upregulation of TGF-β1 and ECM proteins, the expression level of p-Smad2 was increased by chronic DDC feeding in the DDC group (Figure 8). Melittin treatment attenuated the expression of p-Smad2 in the DDC + Mel group. Taken together, these results show that melittin might protect liver during DDC feeding by attenuating fibrotic gene expression.


Effects of Melittin Treatment in Cholangitis and Biliary Fibrosis in a Model of Xenobiotic-Induced Cholestasis in Mice.

Kim KH, Sung HJ, Lee WR, An HJ, Kim JY, Pak SC, Han SM, Park KK - Toxins (Basel) (2015)

Melittin inhibits fibrotic changes in DDC-fed mice. Immunohistochemical staining findings demonstrated that melittin effectively suppresses the expression of FSP-1. Representative immunohistochemical images from each study group (five mice per group) (A) NC, normal control group; (B) Mel, melittin (0.1 mg/kg)-treated group with normal diet; (C) DDC, 0.1% DDC-supplemented diet group; (D) DDC + Mel, melittin (0.1 mg/kg)-treated group with 0.1% DDC-supplemented diet; magnification × 200; (E) morphometric assessment of the trichrome staining positive areas. Results are expressed as the mean ± SE of three independent determinations. *p < 0.05 compared to the NC group. †p < 0.05 compared to the Mel group. ‡p < 0.05 compared to the DDC group.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4591642&req=5

toxins-07-03372-f007: Melittin inhibits fibrotic changes in DDC-fed mice. Immunohistochemical staining findings demonstrated that melittin effectively suppresses the expression of FSP-1. Representative immunohistochemical images from each study group (five mice per group) (A) NC, normal control group; (B) Mel, melittin (0.1 mg/kg)-treated group with normal diet; (C) DDC, 0.1% DDC-supplemented diet group; (D) DDC + Mel, melittin (0.1 mg/kg)-treated group with 0.1% DDC-supplemented diet; magnification × 200; (E) morphometric assessment of the trichrome staining positive areas. Results are expressed as the mean ± SE of three independent determinations. *p < 0.05 compared to the NC group. †p < 0.05 compared to the Mel group. ‡p < 0.05 compared to the DDC group.
Mentions: Chronic exposure to injuries in cholangitis becomes a progressive course of cholestatic liver with inflammation and fibrosis of bile ducts. Much attention has been focused on the central role of TGF-β1 upregulation as a prototypical fibrogenic cytokine in liver fibrosis [17]. Western blotting results showed that the expression of TGF-β1 was significantly increased in DDC mice, whereas melittin treatment markedly decreased the expression of TGF-β1 in DDC + Mel livers (Figure 6). The expressions of TGF-β1-regulated ECM protein, fibronectin and vimentin were increased in DDC-fed mice. Treatment with melittin effectively abrogated this increase in the DDC + Mel group. During tissue remodelling in liver fibrosis, FSP-1 is considered a marker of fibroblasts in fibrotic liver. DDC feeding significantly increased the number of cells positive for FSP-1 (Figure 7). However, melittin treatment resulted in a reduction in the FSP-1-positive cells in DDC + Mel livers. Along with the upregulation of TGF-β1 and ECM proteins, the expression level of p-Smad2 was increased by chronic DDC feeding in the DDC group (Figure 8). Melittin treatment attenuated the expression of p-Smad2 in the DDC + Mel group. Taken together, these results show that melittin might protect liver during DDC feeding by attenuating fibrotic gene expression.

Bottom Line: In previous studies, melittin was known for attenuation of hepatic injury, inflammation and hepatic fibrosis.DDC feeding led to increased serum markers of hepatic injury, ductular reaction, induction of pro-inflammatory cytokines and biliary fibrosis.Further studies on the anti-inflammatory capacity of melittin are warranted for targeted therapy in cholangiopathy.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, College of Medicine, Catholic University of Daegu, 3056-6, Daemyung-4-Dong, Nam-gu, Daegu 705-718, Korea. khkim1@cu.ac.kr.

ABSTRACT
Cholangiopathy is a chronic immune-mediated disease of the liver, which is characterized by cholangitis, ductular reaction and biliary-type hepatic fibrosis. There is no proven medical therapy that changes the course of the disease. In previous studies, melittin was known for attenuation of hepatic injury, inflammation and hepatic fibrosis. This study investigated whether melittin provides inhibition on cholangitis and biliary fibrosis in vivo. Feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to mice is a well-established animal model to study cholangitis and biliary fibrosis. To investigate the effects of melittin on cholangiopathy, mice were fed with a 0.1% DDC-containing diet with or without melittin treatment for four weeks. Liver morphology, serum markers of liver injury, cholestasis markers for inflammation of liver, the degree of ductular reaction and the degree of liver fibrosis were compared between with or without melittin treatment DDC-fed mice. DDC feeding led to increased serum markers of hepatic injury, ductular reaction, induction of pro-inflammatory cytokines and biliary fibrosis. Interestingly, melittin treatment attenuated hepatic function markers, ductular reaction, the reactive phenotype of cholangiocytes and cholangitis and biliary fibrosis. Our data suggest that melittin treatment can be protective against chronic cholestatic disease in DDC-fed mice. Further studies on the anti-inflammatory capacity of melittin are warranted for targeted therapy in cholangiopathy.

No MeSH data available.


Related in: MedlinePlus