RAGE and cigarette smoke-induced pulmonary lesions: a chronic study on genetically manipulated mice.

The receptor for advanced glycation end products (RAGE) is a member of the im- munoglobulin superfamily whose expression is up regulated in several conditions such as smoking induced bronchial damage, granulomatous disorders or idiopathic pulmonary fibrosis. It has also been reported that a functional polymorphism (–374 T/A) in the promoter region of the RAGE gene may contribute to increase RAGE expression and it is likely implicated in the development of sarcoidosis. Male transgenic mice over expressing human RAGE wild-type [hRAGE wt+] or mutant (–374 T/A polymorphism) [hRAGE mut+] and their respective littermates [hRAGE wt-, hRAGE mut-] were used in this study. Mice were exposed to either room air or to the smoke of 3 cigarettes/day, 5 days/week for 6 months according to Cavarra et al. (AJRCCM, 2001). After 6 months mice were sacrificed and the lungs processed for histological and morphometrical analysis. Expression of human –374 T/A in hRAGE mut+ mice does result neither in significant phenotypical lung changes nor in enhanced susceptibility to develop pulmonary lesions after chronic smoke exposure. This mutant mouse shows nor- mal lung architecture and develops, after chronic smoke exposure, lung changes similar to those observed in their littermates. On the contrary, mice expressing human wild-type RAGE spontaneously develop emphysema and patchy areas of fibrosis, which significantly get worse after chronic smoke exposure. These results, together with those previously obtained in another study carried out in DBA/2 mice chronically exposed to smoke, strongly suggest an important role for RAGE in certain pathological conditions in which emphysema and fibrosis are associate