Two mouse models for studying smoke-related interstitial lung diseases

Rationale. Some subgroups of interstitial lung diseases, namely desquamative interstitial pneumonia (DIP), respiratory bronchiolitis-associated interstitial pneumonia (RB-ILD), and pulmonary Langerhans cell histiocytosis, are caused by cigarette smoke (CS) in susceptible individuals. Despite smoke-related interstitial lung diseases (SRILDs) have been subjected to extensive investigation during the last years, very little is know about the pathogenetic mechanisms of these diseases and why only a susceptible minority of tobacco smokers develop a clinically significant disease. Methods & Results. We observed that the combination of chronic CS exposure with targeted mutation of genes involved in the expression of factors important for adaptive immune responses (namely p56LcK), or for the modulation of antioxidant genes (such as p66Shc), results in the development of SRILDs. These mice mimic the histopathological traits, which characterise either DIP or RB—ILD in man. As in human RB-ILD, p66Shc KO mice develop after CS exposure patchy lung changes with a bronchiolocentric distribution characterized by pigmented macrophages within bronchiolar lumina, peribronchiolar inflammation and fibrosis. In p56LcK KO mice, chronic macrophage pneumonia is the main feature. Unlike the previous model, the alveolar septal thickening and inflammation in this DIP model tends to be diffuse and uniform from field to field. Species differences notwithstanding, the data obtained in our mice suggest that DIP cannot be regarded as a late stage of RB—ILD but may represent an earlier stage of cryptogenic fibrosing alveolitis. Conclusions. Further studies on these unique animal models may shed light on the pathogenetic mechanisms and the missing links existing among the various SRILDs and can provide valuable information on both the reversibility and the evolution of the lung changes characterising DIP and/or RB—ILD