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The mechanisms and signaling pathways whereby Cd causes pathological peribronchiolar fibrosis, airway remodeling, and subsequent airflow obstruction remain unclear. We aimed to evaluate whether low-dose Cd exposure induces vimentin phosphorylation and Yes-associated protein 1 (YAP1) activation leading to peribronchiolar fibrosis and subsequent airway remodeling. Our data demonstrate that Cd induces myofibroblast differentiation and extracellular matrix (ECM) deposition around small (&lt;2 mm in diameter) airways. Upon Cd exposure, \u03b1-smooth muscle actin (\u03b1-SMA) expression and the production of ECM proteins, including fibronectin and collagen-1, are markedly induced in primary human lung fibroblasts. Cd induces Smad2\/3 activation and the translocation of both Smad2\/3 and Yes-associated protein 1 (YAP1) into the nucleus. In parallel, Cd induces AKT and cdc2 phosphorylation and downstream vimentin phosphorylation at Ser<jats:sup>39<\/jats:sup>and Ser<jats:sup>55<\/jats:sup>, respectively. AKT and cdc2 inhibitors block Cd-induced vimentin fragmentation and secretion in association with inhibition of \u03b1-SMA expression, ECM deposition, and collagen secretion. Furthermore, vimentin silencing abrogates Cd-induced \u03b1-SMA expression and decreases ECM production. Vimentin-deficient mice are protected from Cd-induced peribronchiolar fibrosis and remodeling. These findings identify two specific sites on vimentin that are phosphorylated by Cd and highlight the functional significance of vimentin phosphorylation in YAP1\/Smad3 signaling that mediates Cd-induced peribronchiolar fibrosis and airway remodeling.<\/jats:p>","DOI":"10.1152\/ajplung.00087.2017","type":"journal-article","created":{"date-parts":[[2017,4,28]],"date-time":"2017-04-28T00:20:19Z","timestamp":1493338819000},"page":"L80-L91","source":"Crossref","is-referenced-by-count":40,"title":["Low-dose cadmium exposure induces peribronchiolar fibrosis through site-specific phosphorylation of vimentin"],"prefix":"10.1152","volume":"313","author":[{"given":"Fu Jun","family":"Li","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, 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