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Melatonin or Dark Therapy Reduce Biliary Damage, Inflammation and Liver Fibrosis in a Murine Model of Early Stage Primary Biliary Cholangitis
Author(s) -
Kennedy Lindsey,
Wu Nan,
Francis Heather,
Venter Julie,
Meng Fanyin,
Kyritsi Konstantina,
Zhou Tianhao,
Gaudio Eugenio,
Glaser Shan,
Alpini Gianfranco
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.608.3
Subject(s) - sirius red , cholestasis , medicine , melatonin , hepatic stellate cell , fibrosis , bile duct , endocrinology , intrahepatic bile ducts , pathology , liver injury , gastroenterology
Background Primary biliary cholangitis (PBC) is characterized by increased biliary damage, inflammation and liver fibrosis. Early stage PBC is marked by biliary proliferation, whereas late stage PBC shows ductopenia. We have shown that dominant‐negative transforming growth factor b receptor II (dnTGFβRII) mice at 12 wk of age mimic early stage PBC. We have found that melatonin therapy or prolonged exposure to complete darkness reduces biliary hyperplasia and liver fibrosis in models of cholestasis. However, the impact of melatonin or dark therapy on PBC‐related injury is unknown. The aim of our study was to evaluate the effects of melatonin or dark therapy in a mouse model of early stage PBC. Methods We used background‐matched, male wild‐type (WT) and dnTGFβRII at 12 wk of age that were given drinking water containing melatonin (0.03%) or placed in complete darkness for 1 wk along with the related controls. Liver damage was evaluated by H&E. Intrahepatic bile duct mass (IBDM) was measured by CK‐19 staining. Biliary senescence was evaluated by staining for p16 and p21, and SA‐β‐galactosidase activity. Biliary and liver inflammation were determined by IL‐6 and F4/80 (Kupffer cell marker) staining. Liver fibrosis was determined by Sirius Red staining and immunofluorescence for collagen type‐1a. Hepatic stellate cell (HSC) activation was shown by SYP‐9 and α‐SMA staining. Human control and early stage PBC serum samples were obtained, and serum melatonin levels were measured by EIA. Results dnTGFβRII at 12 wk of age (early stage PBC mouse model) treated with melatonin or complete darkness had decreased (i) IBDM, (ii) biliary senescence, (iii) liver fibrosis, (iv) biliary and liver inflammation, and (v) HSC activation/liver fibrosis. Human early stage PBC samples had decreased serum melatonin levels. Conclusion Inhibition of melatonin signaling perpetuates biliary damage associated with PBC. Restoration of melatonin‐dependent signaling via melatonin treatment or dark therapy may be therapeutic for patients with early stage PBC. Support or Funding Information NIH NIDDK R01, VA Merit This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .