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.
Type
Journal articleSubject
Schistosomiasis mansoniSymmers' fibrosis
cholangiocyte
ductular proliferation
osteopontin
portal hypertension
Adolescent
Adult
Animals
Antigens, Helminth
Bile Ducts
Cell Line
Cell Proliferation
Cells, Cultured
Female
Hepatic Stellate Cells
Host-Parasite Interactions
Humans
Hypertension, Portal
Immunohistochemistry
Kupffer Cells
Liver Cirrhosis
Male
Mice
Middle Aged
Osteopontin
Rats
Reverse Transcriptase Polymerase Chain Reaction
Schistosoma
Schistosomiasis mansoni
Young Adult
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https://hdl.handle.net/10161/11081Published Version (Please cite this version)
10.1042/CS20150117Publication Info
Pereira, Thiago A; Syn, Wing-Kin; Machado, Mariana V; Vidigal, Paula V; Resende, Vivian;
Voieta, Izabela; ... Diehl, Anna Mae (2015). Schistosome-induced cholangiocyte proliferation and osteopontin secretion correlate
with fibrosis and portal hypertension in human and murine schistosomiasis mansoni.
Clin Sci (Lond), 129(10). pp. 875-883. 10.1042/CS20150117. Retrieved from https://hdl.handle.net/10161/11081.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Steven Sok Choi
Associate Professor of Medicine
Hepatic stellate cell biology; Hepatic Fibrogenesis; Liver regeneration
Anna Mae Diehl
Florence McAlister Distinguished Professor of Medicine
Our lab has a long standing interest in liver injury and repair. To learn more about
the mechanisms that regulate this process, we study cultured cells, animal models
of acute and chronic liver damage and samples from patients with various types of
liver disease. Our group also conducts clinical trials in patients with chronic liver
disease. We are particularly interested in fatty liver diseases, such as alcoholic
fatty liver disease and nonalcoholi
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