Oral Angiotensin-(1-7) reversed elastase-induced structural damage and prevented secondary eosinophilic exacerbations in a mouse model of asthma-COPD overlap.
Does oral Angiotensin-(1-7) reverse pulmonary emphysema and prevent eosinophilic exacerbation in a mouse model of asthma-COPD overlap?
Oral Angiotensin-(1-7) reverses structural damage in established emphysema and prevents secondary eosinophilic exacerbations in a preclinical asthma-COPD overlap model.
Abstract Introduction Chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma represent major global health burdens, characterized by persistent inflammation, airway remodeling, and impaired lung function. The coexistence of both conditions, referred to as asthma-COPD overlap (ACO), is associated with frequent exacerbations and limited therapeutic options. The renin-angiotensin system (RAS), particularly its counter-regulatory ACE2/Angiotensin-(1-7)/Mas receptor axis, has emerged as a key modulator of inflammation and tissue remodeling. In this study, we investigated whether oral Angiotensin-(1-7) Ang-(1-7) could reverse established elastase-induced pulmonary emphysema and prevent secondary eosinophilic inflammation triggered by ovalbumin (OVA) sensitization and challenge. Methods Eight-week-old C57BL/6 mice were subjected to three intratracheal instillations of porcine pancreatic elastase (0.2 IU in 30 μL saline) administered at weekly intervals to induce pulmonary emphysema. One week after the final instillation, mice were treated orally with Ang-(1-7) (60 µg/kg/day) complexed with hydroxypropyl-β-cyclodextrin for four consecutive weeks. Following treatment, selected groups were sensitized and challenged with OVA to establish an asthma-emphysema overlap model. Morphometric, molecular, and histological analyses were performed to assess alveolar structure, inflammation, fibrosis, and RAS component expression. Results Ang-(1-7) treatment effectively reversed elastase-induced structural damage, restoring alveolar wall integrity and reducing airspace enlargement to control levels. These effects correlated with normalization of elevated pulmonary Angiotensin II concentrations and upregulation of ACE2 mRNA, confirming reactivation of the protective RAS axis. In the overlap model, OVA sensitization of emphysematous mice markedly intensified inflammation, with elevated eosinophil counts, increased expression of M2 macrophage markers (CD206 and arginase-1), activation of the NLRP3 inflammasome, and induction of cellular senescence markers p53 and p16. Pre-treatment with Ang-(1-7) significantly mitigated these pathological responses, reducing eosinophilia, downregulating NLRP3 and IL-1β expression, and suppressing senescence signaling. Morphometric data revealed that Ang-(1-7) preserved alveolar architecture, reduced epithelial thickening, and limited collagen deposition, demonstrating robust anti-remodeling and anti-fibrotic effects. Conclusion Together, these findings provide novel evidence that oral Ang-(1-7) not only reverses structural damage in established emphysema but also prevents secondary eosinophilic exacerbations associated with asthma-like inflammation. By simultaneously restoring RAS balance, suppressing inflammasome activation, and limiting tissue remodeling, Ang-(1-7) emerges as a promising dual-action therapeutic candidate for the treatment of complex chronic pulmonary phenotypes such as asthma-COPD overlap. This abstract is funded by: None
Bastos et al. (2026) studied Asthma-COPD overlap (ACO). Oral Angiotensin-(1-7) was evaluated on Alveolar structure, inflammation, fibrosis, and RAS component expression. Oral Angiotensin-(1-7) reversed elastase-induced structural damage and prevented secondary eosinophilic exacerbations in a mouse model of asthma-COPD overlap.