Recombinant RAGE antagonist peptide promotes alveolar epithelial cell regeneration via the RAGE/MAPKs/MMP2 pathway in emphysema.

The progression of chronic obstructive pulmonary disease (COPD) results in irreversible pulmonary damage and sustained inflammatory responses. While alternative approaches have been explored, the specific role of alveolar epithelial cells in the pathogenesis of COPD remains unclear. Additionally, the association between emphysema and DAMP-RAGE signaling in COPD patients are not understood. Therefore, this study demonstrates to determine the therapeutic effect of a RAGE antagonist peptide (RAP), which we previously identified on the pathogenesis of COPD. We assessed the expression of RAGE ligands and RAGE binding signaling in COPD patients using GEO data. PPE-induced emphysema mouse model and AGER^-/- mouse were employed, along treated with RAP. The association between RAGE and the development of emphysema was examined in H&E staining and western blot analysis in mouse lung tissue and BALF. We next analyzed the damage caused by oxidative stress and inflammation through CSE and RAP in human alveolar epithelial cell line A549. Our results show that inhibiting of RAGE alleviates emphysema by suppressing inflammation and MMP activity. Inhibition of RAGE in alveolar epithelial cells significantly induced the mitigation of lung injury, independent of macrophage infiltration. Furthermore, it was confirmed that RAP ameliorated CSE-induced oxidative stress, inflammation, and cell cycle arrest in human alveolar epithelial cells. These findings demonstrate that inhibiting RAGE in alveolar epithelial cells suppress lung injury and emphysema by inhibiting oxidative stress-induced inflammation and MMPs, while promoting alveolar epithelial cell proliferation. Furthermore, blocking of the DAMP-RAGE interaction through RAP offers a promising therapeutic approach for mitigating emphysema.