Oral Angiotensin-(1-7) formulation after established elastase-induced emphysema suppresses inflammation and restores lung architecture

BACKGROUND: Chronic obstructive pulmonary disease (COPD), a prevalent age-related condition, ranks among the leading causes of global mortality. It is characterized by chronic inflammation, cellular senescence, and irreversible lung tissue damage, with no curative treatments currently available. Angiotensin-(1-7) [Ang-(1-7)] has demonstrated anti-inflammatory and regenerative potential in preclinical models. This study aimed to investigate the therapeutic effects of oral Ang-(1-7) on senescence, inflammation, and tissue regeneration in a model of elastase-induced pulmonary emphysema. METHODS: Male C57BL/6 mice were subjected to emphysema induction through three intratracheal instillations of porcine pancreatic elastase (PPE). One week after the final elastase instillation, the mice were treated with Ang-(1-7) encapsulated in hydroxypropyl-β-cyclodextrin to enhance its bioavailability. The treatment was administered daily for 4 weeks. Histological assessments, gene expression analysis, and protein quantification through Western blot were performed to evaluate lung architecture, inflammation, and senescence markers. RESULTS: The results showed that elastase exposure led to significant lung damage, including enlarged airspaces, increased collagen deposition and upregulated expression of collagen I/III and MMP9. Markers of inflammation and senescence were significantly elevated in the untreated emphysema group. However, treatment with Ang-(1-7) reversed these changes, reducing collagen deposition, restoring alveolar structure, and suppressing inflammation and senescence. Additionally, Ang-(1-7) modulated key signaling pathways, reactivating the Wnt/β-catenin pathway for tissue regeneration and inhibiting NF-κB activation, critical for inflammation suppression. CONCLUSION: These findings suggest that Ang-(1-7), when administered after disease establishment, demonstrates potential to reverse structural lung damage and suppress chronic inflammation in experimental models, indicating a promising direction for future translational and clinical research in COPD.