{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T23:23:50Z","timestamp":1785281030427,"version":"3.55.0"},"reference-count":56,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,3,16]],"date-time":"2022-03-16T00:00:00Z","timestamp":1647388800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ELKE-NKUA","award":["O974"],"award-info":[{"award-number":["O974"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Microvascular wall abnormalities demonstrated by nailfold capillaroscopy in systemic sclerosis (SSc) may result in microhemorrhagic deposition of erythrocyte-derived iron. Such abnormalities precede fibrosis, which is orchestrated by myofibroblasts. Iron induces endothelial-to-mesenchymal transition in vitro, which is reversed by reactive oxygen species (ROS) scavengers. The conversion of quiescent fibroblasts into profibrotic myofibroblasts has also been associated with ROS-mediated activation of TGF-\u03b21. Given that iron overload predisposes to ROS formation, we hypothesized that the uptake of erythrocyte-derived iron by resident cells promotes fibrosis. Firstly, we show that iron induces oxidative stress in skin-derived and synovial fibroblasts in vitro, as well as in blood mononuclear cells ex vivo. The biological relevance of increased oxidative stress was confirmed by showing the concomitant induction of DNA damage in these cell types. Similar results were obtained in vivo, following intravenous iron administration. Secondly, using magnetic resonance imaging we show an increased iron deposition in the fingers of a patient with early SSc and nailfold microhemorrhages. While a systematic magnetic resonance study to examine tissue iron levels in SSc, including internal organs, is underway, herein we propose that iron may be a pathogenetic link between microvasculopathy and fibrosis and an additional mechanism responsible for increased oxidative stress in SSc.<\/jats:p>","DOI":"10.3390\/life12030430","type":"journal-article","created":{"date-parts":[[2022,3,16]],"date-time":"2022-03-16T03:36:23Z","timestamp":1647401783000},"page":"430","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Microvasculopathy-Related Hemorrhagic Tissue Deposition of Iron May Contribute to Fibrosis in Systemic Sclerosis: Hypothesis-Generating Insights from the Literature and Preliminary Findings"],"prefix":"10.3390","volume":"12","author":[{"given":"Petros P.","family":"Sfikakis","sequence":"first","affiliation":[{"name":"First Department of Propaedeutic Internal Medicine and Joint Academic Rheumatology Program, National and Kapodistrian University of Athens Medical School, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7878-8078","authenticated-orcid":false,"given":"Nikolaos I.","family":"Vlachogiannis","sequence":"additional","affiliation":[{"name":"First Department of Propaedeutic Internal Medicine and Joint Academic Rheumatology Program, National and Kapodistrian University of Athens Medical School, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panagiotis A.","family":"Ntouros","sequence":"additional","affiliation":[{"name":"First Department of Propaedeutic Internal Medicine and Joint Academic Rheumatology Program, National and Kapodistrian University of Athens Medical School, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Mavrogeni","sequence":"additional","affiliation":[{"name":"Onassis Cardiac Surgery Center, 17674 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas G.","family":"Maris","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Crete Medical School, 71003 Heraklion, Greece"},{"name":"Computational BioMedicine Laboratory, Institute of Computer Science, Foundation for Research and Technology-Hellas (FORTH), 70013 Heraklion, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0927-2403","authenticated-orcid":false,"given":"Apostolos H.","family":"Karantanas","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Crete Medical School, 71003 Heraklion, Greece"},{"name":"Computational BioMedicine Laboratory, Institute of Computer Science, Foundation for Research and Technology-Hellas (FORTH), 70013 Heraklion, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2945-1329","authenticated-orcid":false,"given":"Vassilis L.","family":"Souliotis","sequence":"additional","affiliation":[{"name":"First Department of Propaedeutic Internal Medicine and Joint Academic Rheumatology Program, National and Kapodistrian University of Athens Medical School, 11527 Athens, Greece"},{"name":"Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15002","DOI":"10.1038\/nrdp.2015.2","article-title":"Systemic Sclerosis","volume":"1","author":"Allanore","year":"2015","journal-title":"Nat. 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