Inhibition of RAGE Attenuates Cigarette Smoke-Induced Lung Epithelial Cell Damage via RAGE-Mediated Nrf2/DAMP Signaling

Abstract

The oxidative stress and cellular apoptosis by environmental factor including cigarette smoke induces alveolar airway remodeling leading to chronic obstructive pulmonary disease (COPD). Recently, the receptor for advanced glycan end products (RAGE) which is highly expressed in alveolar epithelium is emerging as a biomarker for COPD susceptibility or progression. However, it still remains unknown how RAGE plays a role in cigarette smoke extract (CSE)-exposed human alveolar type II epithelial cell line. Therefore, we determined the efficacy of RAGE-specific antagonist FPS-ZM1 in response to CSE-induced lung epithelial cells. CSE induced the elevated generation of RONS and release of pro-inflammatory cytokines, and impaired the cellular antioxidant defense system. Further, CSE induced the alteration of RAGE distribution via the activation of redox-sensitive DAMP (Damage-associated molecular patterns) signaling through Nrf2 in cells. Although pre-treatment with SB202190 (p38 inhibitor) or SP600125 (JNK inhibitor) failed to recover the alteration of RAGE distribution, treatment of FPS-ZM1 significantly exhibited anti-inflammatory and anti-oxidative/nitrosative effects, also inhibited the activation of redox-sensitive DAMP signaling through Nrf2 (nuclear factor erythroid 2-related factor 2) migration in the presence of CSE. Taken together, our data demonstrate that RAGE and Nrf2 play a pivotal role in maintenance of alveolar epithelial integrity.

Inhibition of the Receptor for Advanced Glycation End-Products in Acute Respiratory Distress Syndrome: A Randomised Laboratory Trial in Piglets

“…A second limitation is that we suggested restored AFC and lung expression of epithelial channels as potential mechanisms for the beneficial effects of RAGE inhibition, but we acknowledge these are only exploratory, hypothesis-generating findings as we did not measure their protein expression in the lung and were unable to precisely characterise the specific pathways by which RAP and sRAGE might alleviate lung injury in ARDS, thus prompting further investigation. Third, we were unable to test additional means of inhibiting RAGE, such as with FPS-ZM1 (a high-affinity specific blocker that inhibits ligand binding to RAGE that was not used in this study for financial reasons) 44 , or multiple routes of administration, doses and timings for treatment with RAP and sRAGE, and whether a RAGE inhibition strategy may reduce lung injury and improve AFC when applied after experimental ARDS is established remains unknown. Furthermore, our findings may hold true only for acid-induced ARDS, so additional validation is warranted in other settings, such as pulmonary and extrapulmonary sepsis (the most frequent cause of ARDS), prior to considering clinical translation into more complex critical care scenarios that frequently combine multiple organ failure.…”

Role of Atypical Chemokines and Chemokine Receptors Pathways in the Pathogenesis of COPD

“…In vitro exposure of a human adenocarcinoma lung epithelial type 2 cell line to cigarette smoke extract increased levels of proinflammatory cytokines such as IL-6, TNF proteins and RAGE expression, whilst decreasing sRAGE levels. Pre-treatment with a RAGE-specific antagonist FPS-ZM1 (500-1000 ng) attenuated the effects of cigarette smoke extract on these cell lines [563].…”

Lung organoids: target cells for understanding respiratory diseases

“…In particular, HLA-A expression was significantly increased in COPD; therefore, they suggested that HLA-A may serve as a diagnostic marker for COPD. In our previous study, we found that the receptor for advanced glycan end products (RAGE) pathway was related with COPD pathology [49,50]. Then, we showed that a RAGE antagonist, FPS-ZM1, can be therapeutic agent via blockade of RAGE-damage-associated molecular patterns (DAMP) signaling.…”