{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T11:37:23Z","timestamp":1790422643166,"version":"4.1.0"},"reference-count":30,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,4,30]],"date-time":"2020-04-30T00:00:00Z","timestamp":1588204800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"italian Ministry of Education, University and Research (MIUR), by the Scientific Independence of young Researchers (SIR) program","award":["RBSI14D5NX"],"award-info":[{"award-number":["RBSI14D5NX"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Oxidative stress linked to vascular damage plays an important role in the pathogenesis of systemic sclerosis (SSc). Indeed, vascular damage at nailfold capillaroscopy in patients with Raynaud\u2019s Phenomenon (RP) is a major risk factor for the development of SSc together with the presence of specific autoantiobodies. Here, we investigated the effects of the phosphodiesterase type 5 inhibitor (PDE5i) sildenafil, currently used in the management of RP, in modulating the proinflammatory response of dermal fibroblasts to oxidative stress in vitro. Human fibroblasts isolated from SSc patients and healthy controls were exposed to exogenous reactive oxygen species (ROS) (100 \u00b5M H2O2), in the presence or absence of sildenafil (1 \u00b5M). Treatment with sildenafil significantly reduced dermal fibroblast gene expression and cellular release of IL-6, known to play a central role in the pathogenesis of tissue damage in SSc and IL-8, directly induced by ROS. This reduction was associated with suppression of STAT3-, ERK-, NF-\u03baB-, and PKB\/AKT-dependent pathways. Our findings support the notion that the employment of PDE5i in the management of RP may be explored for its efficacy in modulating the oxidative stress-induced proinflammatory activation of dermal fibroblasts in vivo and may ultimately aid in the prevention of tissue damage caused by SSc.<\/jats:p>","DOI":"10.3390\/ijms21093161","type":"journal-article","created":{"date-parts":[[2020,5,4]],"date-time":"2020-05-04T14:00:43Z","timestamp":1588600843000},"page":"3161","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Sildenafil Reduces Expression and Release of IL-6 and IL-8 Induced by Reactive Oxygen Species in Systemic Sclerosis Fibroblasts"],"prefix":"10.3390","volume":"21","author":[{"given":"Luigi","family":"Di Luigi","sequence":"first","affiliation":[{"name":"Unit of Endocrinology, Department of Movement, Human and Health Sciences, University of Rome \u201cForo Italico\u201d, 00135 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Sgr\u00f2","sequence":"additional","affiliation":[{"name":"Unit of Endocrinology, Department of Movement, Human and Health Sciences, University of Rome \u201cForo Italico\u201d, 00135 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guglielmo","family":"Duranti","sequence":"additional","affiliation":[{"name":"Unit of Biochemistry and Molecular Biology, Department of Movement, Human and Health Sciences, University of Rome \u201cForo Italico\u201d, 00135 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Sabatini","sequence":"additional","affiliation":[{"name":"Unit of Biochemistry and Molecular Biology, Department of Movement, Human and Health Sciences, University of Rome \u201cForo Italico\u201d, 00135 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9628-0665","authenticated-orcid":false,"given":"Daniela","family":"Caporossi","sequence":"additional","affiliation":[{"name":"Unit of Biology and Genetic, Department of Movement, Human and Health Sciences, University of Rome \u201cForo Italico\u201d, 00135 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Del Galdo","sequence":"additional","affiliation":[{"name":"Division of Rheumatic and Musculoskeletal Diseases, Leeds Institute of Molecular Medicine, University of Leeds, Leeds LS2 9JT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0577-3144","authenticated-orcid":false,"given":"Ivan","family":"Dimauro","sequence":"additional","affiliation":[{"name":"Unit of Biology and Genetic, Department of Movement, Human and Health Sciences, University of Rome \u201cForo Italico\u201d, 00135 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4296-5081","authenticated-orcid":false,"given":"Cristina","family":"Antinozzi","sequence":"additional","affiliation":[{"name":"Unit of Endocrinology, Department of Movement, Human and Health Sciences, University of Rome \u201cForo Italico\u201d, 00135 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1136\/annrheumdis-2018-213257","article-title":"Association of circulating CXCL10 and CXCL11 with systemic sclerosis","volume":"77","author":"Crescioli","year":"2018","journal-title":"Ann. Rheum. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"25568","DOI":"10.1016\/S0021-9258(19)74429-9","article-title":"Regulation of interleukin 8 gene expression by oxidant stress","volume":"268","author":"DeForge","year":"1993","journal-title":"Int. J. Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/s00281-008-0125-4","article-title":"Oxidative stress and the pathogenesis of scleroderma: The Murrell\u2019s hypothesis revisited","volume":"30","author":"Gabrielli","year":"2008","journal-title":"Semin. Immunopathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"87","DOI":"10.2174\/1874312901206010087","article-title":"New insights into the role of oxidative stress in scleroderma fibrosis","volume":"6","author":"Gabrielli","year":"2012","journal-title":"Open Rheumatol. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.3389\/fphys.2018.01177","article-title":"The Role of Oxidative Stress in the Development of Systemic Sclerosis Related Vasculopathy","volume":"9","author":"Abdulle","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.3899\/jrheum.111423","article-title":"Interleukin 6 in systemic sclerosis and potential implications for targeted therapy","volume":"39","author":"Muangchan","year":"2012","journal-title":"J. Rheumatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1164\/ajrccm.150.5.7952565","article-title":"Interleukin-8 and Neutrophils in Systemic Sclerosis with Lung Involvement","volume":"150","author":"Crestani","year":"1994","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/S2665-9913(19)30144-4","article-title":"The identification and management of interstitial lung disease in systemic sclerosis: Evidence-based European consensus statements","volume":"2","author":"Maher","year":"2020","journal-title":"Lancet Rheumatol."},{"key":"ref_9","first-page":"4569826","article-title":"Systemic Sclerosis Pathogenesis and Emerging Therapies, beyond the Fibroblast","volume":"2019","year":"2019","journal-title":"BioMed Res. Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.ajpath.2011.09.013","article-title":"Blockade of interleukin-6 receptor alleviates disease in mouse model of scleroderma","volume":"180","author":"Kitaba","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2408","DOI":"10.1093\/rheumatology\/keq275","article-title":"The skin of patients with systemic sclerosis softened during the treatment with anti-IL-6 receptor antibody tocilizumab","volume":"49","author":"Shima","year":"2010","journal-title":"Rheumatology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2491","DOI":"10.1006\/jmcc.1996.0241","article-title":"Differential modulation of cytokine production by drugs: Implications for therapy in heart failure","volume":"28","author":"Matsumori","year":"1996","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1007\/s40618-018-0977-y","article-title":"The phosphodiesterase 5 inhibitor S decreases the proinflammatory chemokine IL-8 in diabetic cardiomyopathy: In vivo and in vitro evidence","volume":"42","author":"Giannattasio","year":"2019","journal-title":"J. Endocrinol. Investig."},{"key":"ref_14","first-page":"296","article-title":"Increased production of interleukin 6 and interleukin 8 in scleroderma fibroblasts","volume":"25","author":"Kadono","year":"1998","journal-title":"J. Rheumatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"227","DOI":"10.4103\/0973-3698.219076","article-title":"Phosphodiesterase-5 inhibitors: Raynaud\u2019s and beyond","volume":"12","author":"Phatak","year":"2017","journal-title":"Indian J. Rheumatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1007\/s00018-005-4533-5","article-title":"Phosphodiesterase: Overview of protein structures, potential therapeutic applications and recent progress in drug development","volume":"62","author":"Jeon","year":"2005","journal-title":"Cell Mol. Life Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.clim.2015.09.010","article-title":"Sildenafil attenuates the fibrotic phenotype of skin fibroblasts in patients with systemic sclerosis","volume":"161","author":"Higuchi","year":"2015","journal-title":"Clin. Immunol."},{"key":"ref_18","first-page":"456","article-title":"The Role of interleukin-8 in Inflammation and Mechanisms of Regulation","volume":"64","author":"Bickel","year":"1993","journal-title":"J. Periodontol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1080\/15384047.2015.1056409","article-title":"Activation of IL-8 via PI3K\/Akt-dependent pathway is involved in leptin-mediated epithelial-mesenchymal transition in human breast cancer cells","volume":"16","author":"Wang","year":"2015","journal-title":"Cancer Biol. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1136\/annrheumdis-2019-215894","article-title":"Global skin gene expression analysis of early diffuse cutaneous systemic sclerosis shows a prominent innate and adaptive inflammatory profile","volume":"79","author":"Skaug","year":"2020","journal-title":"Ann. Rheum. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"100","DOI":"10.5301\/jsrd.5000240","article-title":"The mighty fibroblast and its utility in scleroderma research","volume":"2","author":"Garret","year":"2017","journal-title":"J. Scleroderma Related Disord."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1161\/01.RES.0000103311.52853.48","article-title":"Regulation of gene expression by cyclic GMP","volume":"93","author":"Pilz","year":"2003","journal-title":"Circ. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2854","DOI":"10.1002\/art.23791","article-title":"Decreased expression of caveolin 1 in patients with systemic sclerosis: Crucial role in the pathogenesis of tissue fibrosis","volume":"58","author":"Galdo","year":"2008","journal-title":"Arthritis Rheum."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1007\/s12020-017-1378-2","article-title":"The phosphodiesterase 5 inhibitor tadalafil regulates lipidic homeostasis in human skeletal muscle cell metabolism","volume":"59","author":"Marampon","year":"2018","journal-title":"Endocrine"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.freeradbiomed.2015.05.035","article-title":"Alpha B-crystallin induction in skeletal muscle cells under redox imbalance is mediated by a JNK-dependent regulatory mechanism","volume":"86","author":"Fittipaldi","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_26","first-page":"1","article-title":"H2AFX and MDC1 promote maintenance of genomic integrity in male germ cells","volume":"20","author":"Testa","year":"2018","journal-title":"J. Cell Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/0006-291X(92)91656-B","article-title":"Phosphorylation of interleukin-6 at serine54: An early event in the secretory pathway in human fibroblasts","volume":"15","author":"May","year":"1992","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.redox.2016.09.008","article-title":"Resistance training and redox homeostasis: Correlation with age-associated genomic changes","volume":"10","author":"Dimauro","year":"2016","journal-title":"Redox Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2523","DOI":"10.1242\/dev.073072","article-title":"Targeted inactivation of nuclear interaction partner of ALK disrupts meiotic prophase","volume":"139","author":"Illert","year":"2012","journal-title":"Development"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1055\/s-0031-1285867","article-title":"Skeletal muscle differentiation: Role of dehydroepiandrosterone sulfate","volume":"43","author":"Ceci","year":"2011","journal-title":"Horm. Metab. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/9\/3161\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:32:19Z","timestamp":1760362339000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/9\/3161"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,30]]},"references-count":30,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2020,5]]}},"alternative-id":["ijms21093161"],"URL":"https:\/\/doi.org\/10.3390\/ijms21093161","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,30]]}}}