The Receptor for Advanced Glycation End Products (RAGE) is a transmembrane receptor of the immunoglobulin superfamily. While vascular RAGE expression is associated with kidney and liver fibrosis, high expression level of RAGE is found under physiological conditions in the lung. In this study RAGE expression in idiopathic pulmonary fibrosis (IPF) was assessed, and the relation of the receptor to functional changes of epithelial cells and pulmonary fibroblasts in the pathogenesis of the disease was investigated. Significant downregulation of RAGE was observed in lung homogenate and alveolar epithelial type II (ATII) cells from IPF patients as well as in bleomycin-treated mice, demonstrated by RT-PCR, western blotting and immunohistochemistry. In vitro, RAGE downregulation was provoked by stimulation of primary human lung fibroblasts and A549 epithelial cells with the pro-inflammatory cytokines, transforming growth factor-1 or tumor necrosis factor-. Blockade of RAGE resulted in impaired cell adhesion, and siRNA induced knock down of RAGE increased cell proliferation and migration of A549 cells and human primary fibroblast in vitro. These results indicate that RAGE serves a protective role in the lung and that loss of the receptor is related to functional changes of pulmonary cell types with the consequences of fibrotic disease.