title: Increased MMP-7 expression in biliary epithelium and serum underpins native liver fibrosis after successful portoenterostomy in biliary atresia.
abstract: The molecular mechanisms underlying progressive liver fibrosis following surgical treatment of biliary atresia (BA) remain unclear. Our aim was to address hepatic gene and protein expression and serum levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) after successful portoenterostomy (PE), and relate them to histological signs of liver injury, clinical follow-up data and biochemical markers of hepatic function. LIver biopsies and serum samples were obtained from 25 children after successful PE at median age of 3.3 years. Serum MMP concentrations were determined by enzyme-linked immune sorbent assay. Hepatic gene expression of MMPs and TIMPs was analyzed using real-time reverse-transcription PCR. Liver expression of MMP-7 and cytokeratin-7 was studied using immunohistochemistry. Despite effective clearance of biochemical and histological cholestasis following PE, BA patients showed increased hepatic gene expression of MMP-7 (29-fold, p < 0.001), MMP-2 (3.1-fold, p < 0.001), MMP-14 (1.7-fold, p = 0.007), and TIMP-1 (1.8-fold, p < 0.001), when compared to controls. Similar to a biliary epithelial marker cytokeratin-7, expression of MMP-7 localized in biliary epithelium of bile ducts and ductal proliferations and periportal hepatocytes and was increased (p < 0.001) in relation to controls. BA patients had 6-fold higher serum levels of MMP-7 (p < 0.001), which correlated positively with hepatic MMP-7 gene (r = 0.548, p = 0.007) and protein (r = 0.532, p = 0.007) expression. Patients showed a positive correlation between biliary MMP-7 expression and Metavir fibrosis stage (r = 0.605, p = 0.001) and portal fibrosis grade (r = 0.606, p = 0.001). Neither similarly increased MMP-7 expression nor correlation with liver fibrosis was observed in patients with intestinal failure-associated liver disease and comparable Metavir stage. In conclusion, our findings support an unique role of altered hepatic expression of MMP-7 in the progression of liver fibrosis after successful PE and introduce a potential therapeutic target to pharmacologically extend native liver survival by inhibiting MMP-7 hyperactivity. Serum MMP-7 may be a valuable postoperative prognostic tool in BA.
authors: Pediatric Surgery and Pediatric Transplantation Surgery, Pediatric Liver and Gut Research Group, Children's Hospital, University of Helsinki and Helsinki University HospitalHelsinkiFinland; Department of SurgeryNorth Karelia Central HospitalJoensuuFinland.
authors: Anna
authors: A
authors: Kerola
authors: Pediatric Surgery and Pediatric Transplantation Surgery, Pediatric Liver and Gut Research Group, Children's Hospital, University of Helsinki and Helsinki University HospitalHelsinkiFinland; Gastroenterological Surgery, University of Helsinki and Helsinki University HospitalHelsinkiFinland.
authors: Hanna
authors: H
authors: Lampela
authors: Pathology, University of Helsinki and Helsinki University Hospital Helsinki Finland.
authors: Jouko
authors: J
authors: Lohi
authors: Pathology, University of Helsinki and Helsinki University Hospital Helsinki Finland.
authors: Päivi
authors: P
authors: Heikkilä
authors: Pediatric Surgery and Pediatric Transplantation Surgery, Pediatric Liver and Gut Research Group, Children's Hospital, University of Helsinki and Helsinki University Hospital Helsinki Finland.
authors: Annika
authors: A
authors: Mutanen
authors: Pathology and Oral Pathology University of Helsinki and Helsinki University Hospital Helsinki Finland.
authors: Jaana
authors: J
authors: Hagström
authors: Oral and Maxillofacial Diseases University of Helsinki and Helsinki University Hospital Helsinki Finland.
authors: Taina
authors: T
authors: Tervahartiala
authors: Oral and Maxillofacial DiseasesUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland; Division of Periodontology, Department of Dental MedicineKarolinska InstitutetHuddingeSweden.
authors: Timo
authors: T
authors: Sorsa
authors: Department of SurgeryUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland; Research Programs Unit, Translational Cancer Biology, University of Helsinki and Helsinki University HospitalHelsinkiFinland.
authors: Caj
authors: C
authors: Haglund
authors: Pediatric Nephrology and Transplantation, University of Helsinki and Helsinki University Hospital Helsinki Finland.
authors: Hannu
authors: H
authors: Jalanko
authors: Pediatric Surgery and Pediatric Transplantation Surgery, Pediatric Liver and Gut Research Group, Children's Hospital, University of Helsinki and Helsinki University Hospital Helsinki Finland.
authors: Mikko P
authors: MP
authors: Pakarinen
keywords: cytokeratin‐7; ductal proliferation; hepatocyte‐to‐cholangiocyte metaplasia; portal fibrosis; serum marker of fibrosis; tissue inhibitor of matrix metalloproteinases