Th2 immune response and respiratory bronchiolitis-associated interstitial lung disease in p66Shc KO smoking mice

Some interstitial lung diseases, namely Desquamative Interstitial Pneumonia, Respiratory Bronchiolitis-associated Interstitial Lung Disease (RB-ILD), and Pul- monary Langerhans cell Histiocytosis, are etiologically linked to cigarette smoke (CS). However, very little is known about the pathogenetic mechanisms and the reason why only a minority of tobacco smokers develop these diseases. The targeted deletion of p66Shc gene, involved in the modulation of antioxidant genes, confers to mice resistance to oxidative stress, extends life span and corre- lates with reduced levels of p53 dependent apoptosis. These mice exposed to CS develop changes similar to those characterizing human RB-ILD. In particular, p66Shc KO (p66Shc–/–) mice develop patchy lung changes with bronchiolocentric distribution characterized by an accumulation of pigmented macrophages within bronchiolar lumina and the adjacent alveoli, peribronchiolar infiltrates of histiocytes and lymphocytes (prevalently CD4+ T and B cells), and patchy areas of peribronchiolar and septal fibrosis. The alveolar macrophages in p66Shc–/– mice are often multinucleated and contain cytoplasmic granules which stain with Prussian blue. At electron microscopy, they show an activated pattern and large amount of siderosomes and residual bodies (aging pigments) in the cytoplasm. About 85-90% of p66Shc–/– macrophages show a Th2 pattern of activation with induction of arginase and chitinase, and suppression of iNOS. A prevailing Th2 dominated immune response in p66Shc–/– mice is confirmed by the presence of inflammatory cell positive for IL-4 and IL-13. These factors may be involved in the pathogenic mechanism(s) leading to RB-ILD.