RAGE Contributes to Postnatal Pulmonary Development and Adult Lung Maintenance Program in Mice

The role of the receptor for advanced glycation end products (RAGE) in promoting inflammatory response through activation of NF-kB pathway is well established. Recent findings indicate that RAGE may have also regulative function in apoptosis, as well as in proliferation, differentiation and cell adhesion. Unlike other organs, lung tissue in adult age and during organ development shows relatively high levels of RAGE expression. Thus a role for the receptor in lung organogenesis and homeostasis may be supposed. To evaluate the role of RAGE in lung development and adult lung homeostasis we generated hemizygous and homozygous transgenic mice overexpressing human RAGE and analyzed their lungs from 4th postnatal day to adult age. Moderate RAGE hyper-expression during lung development influences the secondary septation resulting in an impairment of alveolar morphogenesis leading to significant changes in morphometric parameters such as air spaces number and size of alveolar ducts. An increase of alveolar cell apoptosis and a decrease of cell proliferation is demonstrated by TUNEL reaction, active caspase3 and Ki67 immunohistochemistry. Alteration in elastin organization and deposition, and in TGFβ expression is observed. In homozygous mice, the hyper-expression of RAGE results in histological changes resembling those characterizing human Bronchopulmonary Dysplasia (BPD). RAGE hyper-expression in adult lung is associated with an increase of the alveolar destructive index and a persistent inflammatory status leading to "destructive" emphysema. These results suggest an important role for RAGE in both alveolar development and lung homeostasis, and open new ways for working hypothesis on the pathogenesis of BPD and COPD.