Integrin alphavbeta6 and mediators of extracellular matrix deposition are up-regulated in experimental biliary atresia.
BACKGROUND
Biliary atresia (BA) is a progressive obliteration of the extrahepatic bile ducts resulting in hepatic fibrosis. The underlying mechanisms have not been defined. We used an animal model of BA to evaluate mediators of extracellular matrix (ECM) processing to determine which factors may be involved.


METHODS
Newborn BALB/c mice received an intraperitoneal injection with rhesus rotavirus or saline within 24 h of birth. Livers were harvested on days 7 and 14 for histology and immunohistochemistry (IHC). RNA expression was determined using quantitative real-time PCR. Human liver from patients with BA and those having a resection for nonfibrosing diseases was also evaluated.


RESULTS
In experimental mice, mRNA expression for tissue inhibitor of metalloproteinase (TIMP)-1 and matrix metalloproteinase (MMP)-7 was increased 18-fold and 69-fold, respectively on day 7, with further increases on day 14. On day 14, mRNA expression for plasminogen activator inhibitor (PAI)-1 (38-fold), TIMP-4 (9.5-fold), and MMP-9 (5.5-fold) mRNA was also observed. Furthermore, integrin alpha(v) beta(6) mRNA expression was increased on days 7 (11-fold) and 14 (6-fold). Presence of integrin alpha(v) beta(6) protein was confirmed by IHC in both mouse and human specimens in the proliferating biliary epithelium.


CONCLUSIONS
Our data suggest experimental BA is associated with increased mRNA expression of ECM degradation inhibitors, TIMP-1, PAI-1, and TIMP-4. MMP-7 and MMP-9 expression is also elevated in this model. Furthermore, increased gene expression of integrin alpha(v)beta(6) was demonstrated and IHC confirmed protein expression. Integrin alpha(v)beta(6) or the inhibitors of ECM breakdown may be attractive targets for future treatment strategies.
Nadler
Evan P
EP
Division of Pediatric Surgery, Department of Surgery, New York University School of Medicine, New York, New York 10016, USA. evan.nadler@med.nyu.edu
Patterson
Danielle
D
Violette
Shelia
S
Weinreb
Paul
P
Lewis
Michael
M
Magid
Margaret S
MS
Greco
M Alba
MA
D000818:Animals; D000831:Animals, Newborn; D000951:Antigens, Neoplasm / Q000235:genetics*; D001656:Biliary Atresia / Q000201:enzymology / Q000235:genetics / Q000473:pathology* / Q000821:virology; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000473:pathology*; D007150:Immunohistochemistry; D016023:Integrins / Q000235:genetics*; D020783:Matrix Metalloproteinase 7 / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D015854:Up-Regulation
D000951:Antigens, Neoplasm; D016023:Integrins; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; C073878:integrin alphavbeta6; D020783:Matrix Metalloproteinase 7