Receptors for advanced glycation end-products (RAGE) are multiligand cell-surface receptors detected abundantly in pulmonary tissue. Our previous work revealed increased RAGE expression in cells and lungs exposed to tobacco smoke (1) and that the initiation of RAGE signaling following smoke exposure leads to cytokine expression via pro-inflammatory mechanisms mediated by Ras and NF-kB (2,3). Furthermore, we have discovered important pro-apoptotic embryonic effects when RAGE is genetically upregulated in mice (4,5). RAGE expression is elevated in various pathological states, including chronic obstructive pulmonary disease; however, precise contributions of RAGE to the progression of emphysema and pulmonary inflammation are yet unknown. In the current study we generated a RAGE transgenic mouse (RAGE TG) that conditionally over-expressed RAGE by ATII cells in the respiratory compartment. RAGE was induced from weaning (20 days of age) until sacrifice date at 50, 80, and 110 days (representing 30, 60, and 90 days of RAGE over-expression). H&E staining and mean chord length measurement revealed incremental dilation of alveolar spaces as RAGE over-expression persisted. TUNEL staining and electron microscopy confirmed increased apoptosis and blebbing of alveolar epithelium in lungs from RAGE TG mice when compared to controls. Immunohistochemistry using specific antibodies for matrix metalloproteinase 9 (MMP-9) revealed an overall increase in MMP-9 expression, which correlated with decreased elastin expression in RAGE TG mice. Furthermore, RAGE TG mice manifested significant inflammation measured by elevated bronchoalveolar lavage protein, leukocyte infiltration, and secreted cytokines. These data support the concept that innovative transgenic mice that over-express RAGE may model pulmonary inflammation and alveolar destabilization independent of tobacco smoke. Furthermore, it validates RAGE signaling as a target pathway in the prevention or attenuation of smoke-related inflammatory lung diseases.