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Although this reversible epithelial replacement is almost always observed in association with chronic inflammation, the role of inflammatory mediators in the pathogenesis of squamous metaplasia remains unclear. In the present study, we investigated the implication of cigarette smoke\u2013mediated proinflammatory cytokine up-regulation in the development and treatment of tracheobronchial epithelial hyperplasia and squamous metaplasia. Using immunohistological techniques, we showed a higher epithelial expression of TNF-\u03b1, IL-1\u03b2, and IL-6, as well as an activation of NF-\u03baB and activator protein\u20131\/mitogen-activated protein kinase signaling pathways in the respiratory tract of smoking patients, compared with the normal ciliated epithelium of nonsmoking patients. In addition, we demonstrated that these signaling pathways strongly influence the proliferation and differentiation state of in vitro\u2013generated normal human airway epithelial basal cells. Finally, we exposed mice to cigarette smoke for 16 weeks, and demonstrated that anti\u2013TNF-\u03b1 (etanercept), anti\u2013IL-1\u03b2 (anakinra), and\/or anti\u2013IL-6R (tocilizumab) therapies significantly reduced epithelial hyperplasia and the development of squamous metaplasia. These data highlight the importance of soluble inflammatory mediators in the pathogenesis of tracheobronchial squamous metaplasia. Therefore, the administration of proinflammatory cytokine antagonists may have clinical applications in the management of patients with COPD.<\/jats:p>","DOI":"10.1165\/rcmb.2011-0353oc","type":"journal-article","created":{"date-parts":[[2012,2,17]],"date-time":"2012-02-17T00:25:43Z","timestamp":1329438343000},"page":"67-79","source":"Crossref","is-referenced-by-count":79,"title":["Proinflammatory Cytokines Induce Bronchial Hyperplasia and Squamous Metaplasia in Smokers"],"prefix":"10.1093","volume":"47","author":[{"given":"Michael","family":"Herfs","sequence":"first","affiliation":[{"name":"Laboratory of Experimental Pathology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascale","family":"Hubert","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Pathology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Lise","family":"Poirrier","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, University Hospital of Li\u00e8ge and University Hospital of Mont-Godinne, Catholic University of Louvain, Yvoir, Belgium; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Vandevenne","sequence":"additional","affiliation":[{"name":"Laboratory of Virology and Immunology, GIGA-Signal Transduction, University of Li\u00e8ge, Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginie","family":"Renoux","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Pathology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvette","family":"Habraken","sequence":"additional","affiliation":[{"name":"Laboratory of Virology and Immunology, GIGA-Signal Transduction, University of Li\u00e8ge, Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didier","family":"Cataldo","sequence":"additional","affiliation":[{"name":"Laboratory of Tumor and Development 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