title: Proinflammatory cytokines induce bronchial hyperplasia and squamous metaplasia in smokers: implications for chronic obstructive pulmonary disease therapy.
abstract: Tracheobronchial squamous metaplasia is common in smokers, and is associated with both airway obstruction in chronic obstructive pulmonary disease (COPD) and increased risk of lung cancer. 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-mediated 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-α, IL-1β, and IL-6, as well as an activation of NF-κB and activator protein-1/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-generated normal human airway epithelial basal cells. Finally, we exposed mice to cigarette smoke for 16 weeks, and demonstrated that anti-TNF-α (etanercept), anti-IL-1β (anakinra), and/or anti-IL-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.
authors.affiliation: Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège, Belgium. M.Herfs@ulg.ac.be
authors.forename: Michael
authors.initials: M
authors.lastname: Herfs
authors.forename: Pascale
authors.initials: P
authors.lastname: Hubert
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Poirrier
authors.forename: Patricia
authors.initials: P
authors.lastname: Vandevenne
authors.forename: Virginie
authors.initials: V
authors.lastname: Renoux
authors.forename: Yvette
authors.initials: Y
authors.lastname: Habraken
authors.forename: Didier
authors.initials: D
authors.lastname: Cataldo
authors.forename: Jacques
authors.initials: J
authors.lastname: Boniver
authors.forename: Philippe
authors.initials: P
authors.lastname: Delvenne
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D001980:Bronchi / Q000473:pathology*; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000068800:Etanercept; D006801:Humans; D006965:Hyperplasia; D007074:Immunoglobulin G / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D008679:Metaplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; D007074:Immunoglobulin G; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; D019947:Receptors, Interleukin-6; D018124:Receptors, Tumor Necrosis Factor; D012906:Smoke; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; C502936:tocilizumab; D000068800:Etanercept