A Pathophysiologic Evaluation of the Receptor for Advanced Glycation End Products (RAGE) in the Lung

The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin super-family of cell surface receptors whose activation has been suggested to contribute to various pathologies. RAGE has been primarily studied in diabetes where its upregulation has been linked to disease in the kidney, vasculature, and nervous system. This protein is highly expressed in the lung under normal conditions, but its function is unknown. We therefore investigated the normal function of RAGE in the lung and its pulmonary expression in two disease states.Idiopathic pulmonary fibrosis (IPF) is a debilitating disease with both high morbidity and mortality. Unfortunately, there are currently no effective therapies for IPF necessitating mechanistic insight into the disease pathogenesis. We found that pulmonary fibrosis led to a depletion of RAGE in both animal models and tissue from patients with idiopathic pulmonary fibrosis. In contrast to other diseases in which RAGE signaling promotes pathology, we found that aged RAGE null mice spontaneously develop pulmonary fibrosis-like alterations and more severe fibrosis in response to asbestos injury. In addition, we found that RAGE null mice were fully protected from the fibrotic effects of bleomycin. In addition, we investigated the expression of RAGE in the lungs of diabetic rodents. Diabetes has been shown to alter RAGE expression in a number of tissues that do not normally express RAGE. We hypothesized that diabetes would alter pulmonary RAGE expression and contribute to the susceptibility to pulmonary injury. We found that pulmonary RAGE expression was unaltered in five rodent models suggesting that diabetes does not effect RAGE expression in the lung.Lastly, we identified that RAGE has a very high affinity for components in the basement membrane of the lung. A few RAGE studies suggested that it might serve a role as an adhesion molecule. We found that RAGE extensively colocalized with the alveolar basement membrane and had very high affinity for collagen I, collagen IV, and laminin, but not fibronectin. These findings along with the fact that RAGE null mice spontaneously develop fibrosis suggest a potential homeostatic function of RAGE in the lung. This is in stark contrast to the vast majority of studies, which suggest that its expression is solely pathologic