title: Schistosome-induced cholangiocyte proliferation and osteopontin secretion correlate with fibrosis and portal hypertension in human and murine schistosomiasis mansoni.
abstract: Schistosomiasis is a major cause of portal hypertension worldwide. It associates with portal fibrosis that develops during chronic infection. The mechanisms by which the pathogen evokes these host responses remain unclear. We evaluated the hypothesis that schistosome eggs release factors that directly stimulate liver cells to produce osteopontin (OPN), a pro-fibrogenic protein that stimulates hepatic stellate cells to become myofibroblasts. We also investigated the utility of OPN as a biomarker of fibrosis and/or severity of portal hypertension. Cultured cholangiocytes, Kupffer cells and hepatic stellate cells were treated with soluble egg antigen (SEA); OPN production was quantified by quantitative reverse transcriptase polymerase chain reaction (qRTPCR) and ELISA; cell proliferation was assessed by BrdU (5-bromo-2'-deoxyuridine). Mice were infected with Schistosoma mansoni for 6 or 16 weeks to cause early or advanced fibrosis. Liver OPN was evaluated by qRTPCR and immunohistochemistry (IHC) and correlated with liver fibrosis and serum OPN. Livers from patients with schistosomiasis mansoni (early fibrosis n=15; advanced fibrosis n=72) or healthy adults (n=22) were immunostained for OPN and fibrosis markers. Results were correlated with plasma OPN levels and splenic vein pressures. SEA-induced cholangiocyte proliferation and OPN secretion (P<0.001 compared with controls). Cholangiocytes were OPN (+) in Schistosoma-infected mice and humans. Liver and serum OPN levels correlated with fibrosis stage (mice: r=0.861; human r=0.672, P=0.0001) and myofibroblast accumulation (mice: r=0.800; human: r=0.761, P=0.0001). Numbers of OPN (+) bile ductules strongly correlated with splenic vein pressure (r=0.778; P=0.001). S. mansoni egg antigens stimulate cholangiocyte proliferation and OPN secretion. OPN levels in liver and blood correlate with fibrosis stage and portal hypertension severity.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, U.S.A. Laboratório de Patologia Experimental, Centro de Pesquisas Gonçalo Moniz/FIOCRUZ, Salvador, BA 40296-710, Brazil.
authors.forename: Thiago A
authors.initials: TA
authors.lastname: Pereira
authors.affiliation: Liver Regeneration and Repair Research Group, Institute of Hepatology, Foundation for Liver Research, London WC1E 6HX, U.K. Department of Surgery, Loyola University, Chicago, Maywood, IL 60153, U.S.A.
authors.forename: Wing-Kin
authors.initials: WK
authors.lastname: Syn
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, U.S.A.
authors.forename: Mariana V
authors.initials: MV
authors.lastname: Machado
authors.affiliation: Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG 30130-100, Brazil.
authors.forename: Paula V
authors.initials: PV
authors.lastname: Vidigal
authors.affiliation: Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG 30130-100, Brazil.
authors.forename: Vivian
authors.initials: V
authors.lastname: Resende
authors.affiliation: Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG 30130-100, Brazil.
authors.forename: Izabela
authors.initials: I
authors.lastname: Voieta
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, U.S.A.
authors.forename: Guanhua
authors.initials: G
authors.lastname: Xie
authors.affiliation: Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG 30130-100, Brazil.
authors.forename: Alba
authors.initials: A
authors.lastname: Otoni
authors.affiliation: Laboratório de Patologia Experimental, Centro de Pesquisas Gonçalo Moniz/FIOCRUZ, Salvador, BA 40296-710, Brazil.
authors.forename: Márcia M
authors.initials: MM
authors.lastname: Souza
authors.affiliation: Laboratório de Patologia Experimental, Centro de Pesquisas Gonçalo Moniz/FIOCRUZ, Salvador, BA 40296-710, Brazil.
authors.forename: Elisângela T
authors.initials: ET
authors.lastname: Santos
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, U.S.A.
authors.forename: Isaac S
authors.initials: IS
authors.lastname: Chan
authors.affiliation: Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG 30130-100, Brazil.
authors.forename: Guilherme V M
authors.initials: GV
authors.lastname: Trindade
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, U.S.A.
authors.forename: Steve S
authors.initials: SS
authors.lastname: Choi
authors.affiliation: Life Technologies, Frederick, MD 21704, U.S.A.
authors.forename: Rafal P
authors.initials: RP
authors.lastname: Witek
authors.affiliation: Núcleo de Doenças Infecciosas, Universidade Federal do Espírito Santo, Vitória, ES 29040-091, Brazil.
authors.forename: Fausto E
authors.initials: FE
authors.lastname: Pereira
authors.affiliation: Centers for Disease Control and Prevention, Atlanta, GA 30329, U.S.A.
authors.forename: William E
authors.initials: WE
authors.lastname: Secor
authors.affiliation: Laboratório de Patologia Experimental, Centro de Pesquisas Gonçalo Moniz/FIOCRUZ, Salvador, BA 40296-710, Brazil.
authors.forename: Zilton A
authors.initials: ZA
authors.lastname: Andrade
authors.affiliation: Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG 30130-100, Brazil.
authors.forename: José Roberto
authors.initials: JR
authors.lastname: Lambertucci
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, U.S.A. diehl004@mc.duke.edu.
authors.forename: Anna Mae
authors.initials: AM
authors.lastname: Diehl
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000947:Antigens, Helminth / Q000494:pharmacology; D001652:Bile Ducts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism; D006790:Host-Parasite Interactions; D006801:Humans; D006975:Hypertension, Portal / Q000235:genetics / Q000378:metabolism* / Q000469:parasitology; D007150:Immunohistochemistry; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism* / Q000469:parasitology; D008297:Male; D051379:Mice; D008875:Middle Aged; D053495:Osteopontin / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012547:Schistosoma / Q000502:physiology; D012555:Schistosomiasis mansoni / Q000235:genetics / Q000378:metabolism* / Q000469:parasitology; D055815:Young Adult
chemical_list: D000947:Antigens, Helminth; D053495:Osteopontin
keywords: Schistosomiasis mansoni; Symmers' fibrosis; cholangiocyte; ductular proliferation; osteopontin; portal hypertension