Blockade of RAGE ameliorates elastase-induced emphysema development and progressionviaRAGE-DAMP signaling.
The receptor for advanced glycan end products (RAGE) has been identified as a susceptibility gene for chronic obstructive pulmonary disease (COPD) in genome-wide association studies (GWASs). However, less is known about how RAGE is involved in the pathogenesis of COPD. To determine the molecular mechanism by which RAGE influences COPD in experimental COPD models, we investigated the efficacy of the RAGE-specific antagonist FPS-ZM1 administration inin vivoandin vitroCOPD models. We injected elastase intratracheally and the RAGE antagonist FPS-ZM1 in mice, and the infiltrated inflammatory cells and cytokines were assessed by ELISA. Cellular expression of RAGE was determined in protein, serum, and bronchoalveolar lavage fluid of mice and lungs and serum of human donors and patients with COPD. Downstream damage-associated molecular pattern (DAMP) pathway activationin vivoandin vitroand in patients with COPD was assessed by immunofluorescence staining, Western blot analysis, and ELISA. The expression of membrane RAGE in initiating the inflammatory response and of soluble RAGE acting as a decoy were associated with up-regulation of the DAMP-related signaling pathwayviaNrf2. FPS-ZM1 administration significantly reversed emphysema in the lung of mice. Moreover, FPS-ZM1 treatment significantly reduced lung inflammation inNrf2+/+, but not inNrf2-/-mice. Thus, our data indicate for the first time that RAGE inhibition has an essential protective role in COPD. Our observation of RAGE inhibition provided novel insight into its potential as a therapeutic target in emphysema/COPD.-Lee, H., Park, J.-R., Kim, W. J., Sundar, I. K., Rahman, I., Park, S.-M., Yang. S.-R. Blockade of RAGE ameliorates elastase-induced emphysema development and progressionviaRAGE-DAMP signaling.
Department of Thoracic and Cardiovascular Surgery, Kangwon National University, Chuncheon, South Korea.
Hanbyeol
H
Lee
Department of Thoracic and Cardiovascular Surgery, Kangwon National University, Chuncheon, South Korea.
Jeong-Ran
JR
Park
Department of Internal Medicine, Kangwon National University, Chuncheon, South Korea; and.
Woo Jin
WJ
Kim
Department of Environmental Medicine, University of Rochester Medical Center, Rochester, New York, USA.
Isaac K
IK
Sundar
Department of Environmental Medicine, University of Rochester Medical Center, Rochester, New York, USA.
Irfan
I
Rahman
Department of Thoracic and Cardiovascular Surgery, Kangwon National University, Chuncheon, South Korea.
Sung-Min
SM
Park
Department of Thoracic and Cardiovascular Surgery, Kangwon National University, Chuncheon, South Korea; seran.yang@gmail.com.
Se-Ran
SR
Yang
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000378:metabolism; D008810:Mice, Inbred C57BL; D010196:Pancreatic Elastase / Q000494:pharmacology*; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000378:metabolism*; D000067759:Receptor for Advanced Glycation End Products / Q000037:antagonists & inhibitors*; D015854:Up-Regulation
C000593871:AGER protein, human; C000593873:Ager protein, mouse; D016207:Cytokines; D000067759:Receptor for Advanced Glycation End Products; D010196:Pancreatic Elastase
COPD; FPS-ZM1; Nrf2; emphysema