Mouse models for studying respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) and desquamative interstitial pneumonia (DIP)

Some subgroups of interstitial lung diseases, namely DIP, 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 known about the pathogenetic mechanisms of these diseases and why only a susceptible minority of tobacco smokers develop a clinically significant disease. 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 (p56LcK), or for the modulation of antioxidant genes (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 inflam- mation 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. Further studies on these unique animal models may shed light on the pathogenetic mechanisms, reversibility and evolution of DIP and/or RB-ILD. Funded by: MURST, Rome, Italy