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A Novel Murine Model of Primary Sclerosing Cholangitis Associated Inflammatory Bowel Disease
Author(s) -
Battista Kayla Danae,
Shearn Colin T,
Alexeev Erica E,
Glover Louise E,
Petersen Dennis R,
Colgan Sean P,
Fennimore Blair P
Publication year - 2017
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.31.1_supplement.469.1
Subject(s) - primary sclerosing cholangitis , medicine , inflammatory bowel disease , gastroenterology , ulcerative colitis , primary biliary cirrhosis , fibrosis , inflammation , colitis , cirrhosis , disease
Primary Sclerosing Cholangitis (PSC) is a progressive cholestatic liver disease characterized by biliary inflammation, fibrosis, and stricturing of the intra and extra‐hepatic bile ducts. Progressive disease leads to recurrent cholangitis, biliary cirrhosis, and increased risk of cholangiocarcinoma. PSC carries a strong association with inflammatory bowel disease (IBD) occurring in approximately 80% of patients. PSC associated IBD (PSC‐IBD) displays a unique phenotype characterized by pan‐colonic distribution, right side predominant inflammation, and increased risk of colorectal cancer compared to non‐PSC IBD. The frequent association and unique phenotype of PSC‐IBD suggests distinctive underlying disease mechanisms from other models of chronic liver disease or IBD alone. Multidrug resistance protein 2 (Mdr2) knockout mice develop spontaneous cholestatic liver injury and fibrosis mirroring human PSC, however there are currently no established PSC‐IBD models of combined cholestatic liver injury and IBD. Though Mdr2−/− mice do not display overt evidence of colonic inflammation at baseline, PCR analysis of whole colon tissue reveals elevated levels of pro‐inflammatory cytokines (KC, TNFα, IL‐1β, and IL‐6). We subjected Mdr2−/− mice to DSS colitis as a novel combined model of PSC‐IBD. In this model, Mdr2−/−/DSS mice display increased disease susceptibility characterized by worsened weight‐loss, decreased colon length, and increased histologic damage in the colon. Additionally, colonic and portal serum levels of pro‐inflammatory cytokines (KC, IL‐6, IL‐1β, and IL‐12p70) were significantly increased as compared to C57BL/6 colitis controls. Baseline elevations in colonic levels of pro‐inflammatory cytokines in Mdr2−/− mice along with increased colitis susceptibility in the Mdr2−/−/DSS model suggests an important role for interdependent signaling pathways originating from liver‐intestine crosstalk mechanisms in mediating intestinal injury in this novel murine model of PSC‐IBD. Support or Funding Information NIH 095491 and 5R37AA009300‐20 (DRP)