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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 cholangiocyte proliferation in DDC-fed mice. Immunofluorescence staining shows co-localization of PCNA staining with CK-7 (arrow head) following DDC treatment. Immunofluorescence staining results demonstrated that melittin effectively suppresses the expression of PCNA. CK-7 and PCNA immune complexes were detected by anti-mouse FITC (green) and anti-rabbit Texas red (red). Nuclei were counterstained with Hoechst 33342 (blue). Representative immunofluorescence staining images from each study group ((A–C) DDC group; (D–F) DDC + Mel group). Scale bar = 20 μm.
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toxins-07-03372-f009: Melittin inhibits cholangiocyte proliferation in DDC-fed mice. Immunofluorescence staining shows co-localization of PCNA staining with CK-7 (arrow head) following DDC treatment. Immunofluorescence staining results demonstrated that melittin effectively suppresses the expression of PCNA. CK-7 and PCNA immune complexes were detected by anti-mouse FITC (green) and anti-rabbit Texas red (red). Nuclei were counterstained with Hoechst 33342 (blue). Representative immunofluorescence staining images from each study group ((A–C) DDC group; (D–F) DDC + Mel group). Scale bar = 20 μm.

Mentions: Proliferating cholangiocytes are characteristic for DDC-fed mice and are a source of growth factors, chemokines, cytokines and other soluble factors. Cholangiocytes as specialized epithelial cells that line the biliary tree are considered as pace markers of biliary fibrosis [18]. Cholangiocyte-specific markers, including CK-7, are expressed in the epithelial cells of bile ductules in enlarged portal tracts. Chronic DDC feeding resulted in a comparable amount of ductular reaction and an increased number of CK-7- and PCNA-positive cells (Figure 9). In contrast, melittin treatment significantly suppressed the proliferation of cholangiocytes, which was shown as the expression of PCNA-positive cells in DDC + Mel livers. In summary, these data proved the ability of melittin to suppress cholangiocyte proliferation in response of DDC-induced liver injury and liver fibrosis.


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 cholangiocyte proliferation in DDC-fed mice. Immunofluorescence staining shows co-localization of PCNA staining with CK-7 (arrow head) following DDC treatment. Immunofluorescence staining results demonstrated that melittin effectively suppresses the expression of PCNA. CK-7 and PCNA immune complexes were detected by anti-mouse FITC (green) and anti-rabbit Texas red (red). Nuclei were counterstained with Hoechst 33342 (blue). Representative immunofluorescence staining images from each study group ((A–C) DDC group; (D–F) DDC + Mel group). Scale bar = 20 μm.
© Copyright Policy
Related In: Results  -  Collection

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

toxins-07-03372-f009: Melittin inhibits cholangiocyte proliferation in DDC-fed mice. Immunofluorescence staining shows co-localization of PCNA staining with CK-7 (arrow head) following DDC treatment. Immunofluorescence staining results demonstrated that melittin effectively suppresses the expression of PCNA. CK-7 and PCNA immune complexes were detected by anti-mouse FITC (green) and anti-rabbit Texas red (red). Nuclei were counterstained with Hoechst 33342 (blue). Representative immunofluorescence staining images from each study group ((A–C) DDC group; (D–F) DDC + Mel group). Scale bar = 20 μm.
Mentions: Proliferating cholangiocytes are characteristic for DDC-fed mice and are a source of growth factors, chemokines, cytokines and other soluble factors. Cholangiocytes as specialized epithelial cells that line the biliary tree are considered as pace markers of biliary fibrosis [18]. Cholangiocyte-specific markers, including CK-7, are expressed in the epithelial cells of bile ductules in enlarged portal tracts. Chronic DDC feeding resulted in a comparable amount of ductular reaction and an increased number of CK-7- and PCNA-positive cells (Figure 9). In contrast, melittin treatment significantly suppressed the proliferation of cholangiocytes, which was shown as the expression of PCNA-positive cells in DDC + Mel livers. In summary, these data proved the ability of melittin to suppress cholangiocyte proliferation in response of DDC-induced liver injury and liver fibrosis.

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