Pulmonary emphysema is characterized by persistent
inflammation and progressive alveolar destruction. The
receptor for advanced glycation end-products (RAGE) is a multiligand
cell surface receptor reported to be involved in the process of acute alveolar epithelial cell injury. However, studies that address the role of RAGE in
pulmonary emphysema are inconclusive. We investigated the role of RAGE in the development of
elastase-induced
pulmonary inflammation and
emphysema in mice. RAGE-sufficient (RAGE(+/+)) mice and RAGE-deficient (RAGE(-/-)) mice were treated with intratracheal
elastase on Day 0. Airway
inflammation, static lung compliance, lung histology, and the levels of neutrophil-related
chemokine and proinflammatory
cytokines in bronchoalveolar lavage fluid were determined on Days 4 and 21. Neutrophilia in bronchoalveolar lavage fluid, seen in
elastase-treated RAGE(+/+) mice, was reduced in
elastase-treated RAGE(-/-) mice on Day 4, and was associated with decreased levels of keratinocyte
chemoattractant, macrophage inflammatory protein-2, and IL-1β. Static lung compliance values and emphysematous changes in the lung tissue were decreased in RAGE(-/-) mice compared with RAGE(+/+) mice on Day 21 after
elastase treatment. Experiments using irradiated, bone marrow-chimeric mice showed that the mice expressing RAGE on radioresistant structural cells, but not hematopoietic cells, developed
elastase-induced neutrophilia and emphysematous change in the lung. In contrast, mice expressing RAGE on hematopoietic cells, but not radioresistant structural cells, showed reduced neutrophilia and emphysematous change in the lung. These data identify the importance of RAGE expressed on lung structural cells in the development of
elastase-induced
pulmonary inflammation and
emphysema. Thus, RAGE represents a novel therapeutic target for preventing
pulmonary emphysema.