{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T23:17:18Z","timestamp":1774480638640,"version":"3.50.1"},"reference-count":37,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2012,11,1]],"date-time":"2012-11-01T00:00:00Z","timestamp":1351728000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"NIH","award":["R01 DK077794"],"award-info":[{"award-number":["R01 DK077794"]}]},{"name":"NIH","award":["5K08 DK080980"],"award-info":[{"award-number":["5K08 DK080980"]}]},{"DOI":"10.13039\/501100002425","name":"Brazilian government","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002425","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2013,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Schistosomiasis mansoni is a major cause of portal fibrosis and portal hypertension. The Hedgehog pathway regulates fibrogenic repair in some types of liver injury.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aims<\/jats:title><jats:p>Determine if Hedgehog pathway activation occurs during fibrosis progression in schistosomiasis and to determine if macrophage\u2010related mechanisms are involved.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Immunohistochemistry was used to characterize the cells that generate and respond to Hedgehog ligands in 28 liver biopsies from patients with different grades of schistosomiasis fibrosis staged by ultrasound. Cultured macrophages (RAW264.7 and primary rat Kupffer cells) and primary rat liver sinusoidal endothelial cells (LSEC) were treated with schistosome egg antigen (SEA) and evaluated using q<jats:styled-content style=\"fixed-case\">RT<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">PCR<\/jats:styled-content>. Inhibition of the Hedgehog pathway was used to investigate its role in alternative activation of macrophages (M2) and vascular tube formation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Patients with schistosomiasis expressed more ligands (Shh and Ihh) and target genes (Patched and Gli2) than healthy individuals. Activated LSEC and myofibroblasts were Hedgehog responsive [Gli2(+)] and accumulated in parallel with fibrosis stage (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Double IHC for Ihh\/CD68 showed that Ihh(+) cells were macrophages. <jats:italic>In vitro<\/jats:italic> studies demonstrated that SEA\u2010stimulated macrophages to express Ihh and Shh <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content> (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Conditioned media from such macrophages induced luciferase production by Shh\u2010LightII cells (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) and Hedgehog inhibitors blocked this effect (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001). SEA\u2010treated macrophages also up\u2010regulated their own expression of M2 markers, and Hh pathway inhibitors abrogated this response (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01). Inhibition of the Hedgehog pathway in LSEC blocked SEA\u2010induced migration and tube formation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">SEA<\/jats:styled-content> stimulates liver macrophages to produce Hh ligands, which promote alternative activation of macrophages, fibrogenesis and vascular remodelling in schistosomiasis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.12016","type":"journal-article","created":{"date-parts":[[2012,10,9]],"date-time":"2012-10-09T02:36:53Z","timestamp":1349750213000},"page":"149-161","source":"Crossref","is-referenced-by-count":59,"title":["Macrophage\u2010derived hedgehog ligands promotes fibrogenic and angiogenic responses in human schistosomiasis mansoni"],"prefix":"10.1111","volume":"33","author":[{"given":"Thiago A.","family":"Pereira","sequence":"first","affiliation":[{"name":"Division of Gastroenterology Department of Medicine Duke University Medical Center Durham NC 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