[en] 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. Whereas this reversible epithelial replacement is almost always observed in association with chronic inflammation, the role of inflammatory mediators in the pathogenesis of squamous metaplasia is still unclear. In the present study, we investigated the implication of cigarette smoke-mediated pro-inflammatory cytokine up-regulation in the development and treatment of tracheobronchial epithelial hyperplasia and squamous metaplasia. By using immunohistological techniques, we showed a higher epithelial expression of TNFalpha, IL-1beta and IL-6 as well as an activation of NF-kappaB and AP-1/MAPK signalling pathways in the respiratory tract of smoking patients compared to the normal ciliated epithelium of non-smoking patients. In addition, we demonstrated that these signalling pathways strongly influence the proliferation and the 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-TNFalpha (etanercept), anti-IL-1beta (anakinra) and/or anti-IL-6R (tocilizumab) therapies significantly reduced epithelial hyperplasia and squamous metaplasia development. These data highlight the importance of soluble inflammatory mediators in the pathogenesis of tracheobronchial squamous metaplasia. Therefore, administration of pro-inflammatory cytokine antagonists may have clinical application in the management of COPD patients.
Disciplines :
Oncology
Author, co-author :
Herfs, Michael ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Hubert, Pascale ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Cataldo, Didier ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biochimie et physiologie générales, humaines et path.
Boniver, Jacques ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Delvenne, Philippe ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
Language :
English
Title :
Proinflammatory Cytokines Induce Bronchial Hyperplasia and Squamous Metaplasia in Smokers: Implications for chronic obstructive pulmonary disease therapy.
Publication date :
2012
Journal title :
American Journal of Respiratory Cell and Molecular Biology
ISSN :
1044-1549
eISSN :
1535-4989
Publisher :
American Thoracic Society, New York, United States - New York
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