Emphysema requires the receptor for advanced glycation end-products triggering on structural cells

Koichi Waseda, Nobuaki Miyahara, Akihiko Taniguchi, Etsuko Kurimoto, Genyo Ikeda, Hikari Koga, Utako Fujii, Yasuhiko Yamamoto, Erwin W Gelfand, Hiroshi Yamamoto, Mitsune Tanimoto, Arihiko Kanehiro
American Journal of Respiratory Cell and Molecular Biology 2015, 52 (4): 482-91
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.

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