{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T08:51:00Z","timestamp":1790412660249,"version":"4.1.0"},"reference-count":42,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2016,4,27]],"date-time":"2016-04-27T00:00:00Z","timestamp":1461715200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2016,5]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p><jats:bold> Fibrocytes are collagen\u2010producing leukocytes that accumulate in patients with systemic sclerosis (SSc; scleroderma)\u2013related interstitial lung disease (ILD) via unknown mechanisms that have been associated with altered expression of neuroimmune proteins. The extracellular matrix (ECM) influences cellular phenotypes. However, a relationship between the lung ECM and fibrocytes in SSc has not been explored. The aim of this study was to use a novel translational platform based on decellularized human lungs to determine whether the lung ECM of patients with scleroderma controls the development of<\/jats:bold> <jats:bold>fibrocytes from peripheral blood mononuclear cells.<\/jats:bold><\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p><jats:bold> We performed biomechanical evaluation of decellularized scaffolds prepared from lung explants from healthy control subjects and patients with scleroderma, using tensile testing and biochemical and proteomic analysis. Cells obtained from healthy controls and patients with SSc\u2010related ILD were cultured on these scaffolds, and CD45+pro\u2010ColI\u03b11+ cells meeting the criteria for fibrocytes were quantified. The contribution of the neuromolecule netrin\u20101 to fibrosis was assessed using neutralizing antibodies in this system and by administering bleomycin via inhalation to netrin\u20101<jats:sup>+\/\u2212<\/jats:sup> mice.<\/jats:bold><\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Compared with control lung scaffolds, lung scaffolds from patients with SSc\u2010related ILD showed aberrant anatomy, enhanced stiffness, and abnormal ECM composition. Culture of control cells in lung scaffolds from patients with SSc\u2010related ILD increased production of pro\u2010ColI\u03b11+ cells, which was stimulated by enhanced stiffness and abnormal ECM composition. Cells from patients with SSc\u2010related ILD demonstrated increased pro\u2010ColI\u03b11 responsiveness to lung scaffolds from scleroderma patients but not enhanced stiffness. Enhanced detection of netrin\u20101\u2013expressing CD14<jats:sup>low<\/jats:sup> cells in patients with SSc\u2010related ILD was observed, and antibody\u2010mediated netrin\u20101 neutralization attenuated detection of CD45+pro\u2010ColI\u03b11+ cells in all settings. Netrin\u20101<jats:sup>+\/\u2212<\/jats:sup> mice were protected against bleomycin\u2010induced lung fibrosis and fibrocyte accumulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Factors present in the lung matrices of patients with scleroderma regulate fibrocyte accumulation via a netrin\u20101\u2013dependent pathway. Netrin\u20101 regulates bleomycin\u2010induced pulmonary fibrosis in mice. Netrin\u20101 might be a novel therapeutic target in SSc\u2010related ILD.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.39575","type":"journal-article","created":{"date-parts":[[2016,1,10]],"date-time":"2016-01-10T12:36:41Z","timestamp":1452429401000},"page":"1251-1261","source":"Crossref","is-referenced-by-count":62,"title":["Netrin\u20101 Regulates Fibrocyte Accumulation in the Decellularized Fibrotic Sclerodermatous Lung Microenvironment and in Bleomycin\u2010Induced Pulmonary Fibrosis"],"prefix":"10.1002","volume":"68","author":[{"given":"Huanxing","family":"Sun","sequence":"first","affiliation":[{"name":"Yale University School of Medicine New Haven Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangyang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Yale University School of Medicine New Haven 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