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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

Effect of melittin in DDC-induced liver fibrosis. Hematoxylin and eosin (H&E) staining results show that melittin effectively suppresses inflammation and ductular reaction (arrowheads in (C,D)) in response of DDC feeding. Representative H&E 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.
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toxins-07-03372-f001: Effect of melittin in DDC-induced liver fibrosis. Hematoxylin and eosin (H&E) staining results show that melittin effectively suppresses inflammation and ductular reaction (arrowheads in (C,D)) in response of DDC feeding. Representative H&E 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.

Mentions: After four weeks of DDC feeding, liver showed ductules and small bile ducts, which frequently contained pigment plugs (Figure 1). Additionally, pronounced hepatic inflammatory response was observed near bile ducts with predominating neutrophil granulocytes. Furthermore, spontaneous DDC feeding resulted in the deposition of collagen fibres near fibrous septae and expanded bile ducts (Figure 2). These changes were improved by melittin treatment. The DDC + melittin (Mel) group showed the reduction of collagen deposition. DDC feeding also resulted in increased serum AST and ALT levels as an indicator of hepatocyte injury followed by significant elevations of cholestasis parameters of AP and bilirubin. Serum AST and ALT revealed no significant differences between DDC mice and DDC + Mel mice. However, DDC + Mel mice showed significantly lower serum AP and bilirubin levels (Figure 3). These results suggest that melittin treatment effects a decreased susceptibility of cholestasis in DDC-fed mice.


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)

Effect of melittin in DDC-induced liver fibrosis. Hematoxylin and eosin (H&E) staining results show that melittin effectively suppresses inflammation and ductular reaction (arrowheads in (C,D)) in response of DDC feeding. Representative H&E 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.
© Copyright Policy
Related In: Results  -  Collection

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

toxins-07-03372-f001: Effect of melittin in DDC-induced liver fibrosis. Hematoxylin and eosin (H&E) staining results show that melittin effectively suppresses inflammation and ductular reaction (arrowheads in (C,D)) in response of DDC feeding. Representative H&E 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.
Mentions: After four weeks of DDC feeding, liver showed ductules and small bile ducts, which frequently contained pigment plugs (Figure 1). Additionally, pronounced hepatic inflammatory response was observed near bile ducts with predominating neutrophil granulocytes. Furthermore, spontaneous DDC feeding resulted in the deposition of collagen fibres near fibrous septae and expanded bile ducts (Figure 2). These changes were improved by melittin treatment. The DDC + melittin (Mel) group showed the reduction of collagen deposition. DDC feeding also resulted in increased serum AST and ALT levels as an indicator of hepatocyte injury followed by significant elevations of cholestasis parameters of AP and bilirubin. Serum AST and ALT revealed no significant differences between DDC mice and DDC + Mel mice. However, DDC + Mel mice showed significantly lower serum AP and bilirubin levels (Figure 3). These results suggest that melittin treatment effects a decreased susceptibility of cholestasis in DDC-fed mice.

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