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Schistosome-induced cholangiocyte proliferation and osteopontin secretion correlate with fibrosis and portal hypertension in human and murine schistosomiasis mansoni.
Clin Sci (Lond) 2015; 129(10):875-83CS

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+Show Affiliations

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.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.Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, U.S.A.Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG 30130-100, Brazil.Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG 30130-100, Brazil.Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG 30130-100, Brazil.Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, U.S.A.Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG 30130-100, Brazil.Laboratório de Patologia Experimental, Centro de Pesquisas Gonçalo Moniz/FIOCRUZ, Salvador, BA 40296-710, Brazil.Laboratório de Patologia Experimental, Centro de Pesquisas Gonçalo Moniz/FIOCRUZ, Salvador, BA 40296-710, Brazil.Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, U.S.A.Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG 30130-100, Brazil.Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, U.S.A.Life Technologies, Frederick, MD 21704, U.S.A.Núcleo de Doenças Infecciosas, Universidade Federal do Espírito Santo, Vitória, ES 29040-091, Brazil.Centers for Disease Control and Prevention, Atlanta, GA 30329, U.S.A.Laboratório de Patologia Experimental, Centro de Pesquisas Gonçalo Moniz/FIOCRUZ, Salvador, BA 40296-710, Brazil.Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG 30130-100, Brazil.Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, U.S.A. diehl004@mc.duke.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26201095

Citation

Pereira, Thiago A., et al. "Schistosome-induced Cholangiocyte Proliferation and Osteopontin Secretion Correlate With Fibrosis and Portal Hypertension in Human and Murine Schistosomiasis Mansoni." Clinical Science (London, England : 1979), vol. 129, no. 10, 2015, pp. 875-83.
Pereira TA, Syn WK, Machado MV, et al. Schistosome-induced cholangiocyte proliferation and osteopontin secretion correlate with fibrosis and portal hypertension in human and murine schistosomiasis mansoni. Clin Sci. 2015;129(10):875-83.
Pereira, T. A., Syn, W. K., Machado, M. V., Vidigal, P. V., Resende, V., Voieta, I., ... Diehl, A. M. (2015). Schistosome-induced cholangiocyte proliferation and osteopontin secretion correlate with fibrosis and portal hypertension in human and murine schistosomiasis mansoni. Clinical Science (London, England : 1979), 129(10), pp. 875-83. doi:10.1042/CS20150117.
Pereira TA, et al. Schistosome-induced Cholangiocyte Proliferation and Osteopontin Secretion Correlate With Fibrosis and Portal Hypertension in Human and Murine Schistosomiasis Mansoni. Clin Sci. 2015;129(10):875-83. PubMed PMID: 26201095.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Schistosome-induced cholangiocyte proliferation and osteopontin secretion correlate with fibrosis and portal hypertension in human and murine schistosomiasis mansoni. AU - Pereira,Thiago A, AU - Syn,Wing-Kin, AU - Machado,Mariana V, AU - Vidigal,Paula V, AU - Resende,Vivian, AU - Voieta,Izabela, AU - Xie,Guanhua, AU - Otoni,Alba, AU - Souza,Márcia M, AU - Santos,Elisângela T, AU - Chan,Isaac S, AU - Trindade,Guilherme V M, AU - Choi,Steve S, AU - Witek,Rafal P, AU - Pereira,Fausto E, AU - Secor,William E, AU - Andrade,Zilton A, AU - Lambertucci,José Roberto, AU - Diehl,Anna Mae, Y1 - 2015/07/21/ PY - 2015/02/05/received PY - 2015/07/21/accepted PY - 2015/7/23/entrez PY - 2015/7/23/pubmed PY - 2015/11/18/medline KW - Schistosomiasis mansoni KW - Symmers' fibrosis KW - cholangiocyte KW - ductular proliferation KW - osteopontin KW - portal hypertension SP - 875 EP - 83 JF - Clinical science (London, England : 1979) JO - Clin. Sci. VL - 129 IS - 10 N2 - 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. SN - 1470-8736 UR - https://www.unboundmedicine.com/medline/citation/26201095/Schistosome_induced_cholangiocyte_proliferation_and_osteopontin_secretion_correlate_with_fibrosis_and_portal_hypertension_in_human_and_murine_schistosomiasis_mansoni_ L2 - https://portlandpress.com/clinsci/article-lookup/doi/10.1042/CS20150117 DB - PRIME DP - Unbound Medicine ER -