FPS-ZM1-induced blocking of RAGE alleviates elastase-induced emphysema development by preventing RAGE-DAMP-Nrf2 signaling

Introduction: A receptor for advanced glycation end products (RAGE) has been identified as a susceptibility gene for emphysema/chronic obstructive pulmonary disease (COPD) in genome-wide association studies (GWAS). However, less is known how RAGE is involved in the pathogenesis of COPD. Aim: In this study, we aimed to determine the molecular mechanism by which RAGE influences COPD and to assess the efficacy of RAGE-specific antagonist FPS-ZM1 administration in in vivo and in vitro COPD model. Methods: We injected intratracheally porcine pancreatic elastase (PPE) and RAGE antagonist FPS-ZM1 in mice. Inflammatory cells and cytokine were assessed by ELISA. The expression of RAGE was determined in protein, serum and bronchoalveolar (BAL) fluid of mice. Downstream DAMP pathway activation in vivo, in vitro and patients with COPD was assessed using immunofluorescence, western blotting, and ELISA. Results: we investigated the efficacy of RAGE-specific antagonist FPS-ZM1 administration in in vivo and in vitro COPD model. FPS-ZM1 reversed airspace enlargement and inflammation in emphysema mice. Moreover, we found that expression of membrane RAGE and soluble RAGE was associated with up-regulation of damage-associated molecular patterns (DAMP)-related signaling pathway via NF-E2 related factor 2 (Nrf2). FPS-ZM1 treatment significantly reduced lung inflammation in Nrf2+/+, but not in Nrf2-/- mice. Conclusions: Our data indicated for the first time that RAGE inhibition has an essential protective role in COPD. Our observation provided new insight into the therapeutic target in emphysema/COPD. Acknowledgments: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (NRF-2014R1A2A2A01003737)