Targeting protective renin-angiotensin system pathways in pulmonary emphysema: Preclinical evidence for resolving...

Chronic obstructive pulmonary disease (COPD) remains one of the leading causes of morbidity and mortality worldwide and still lacks effective disease-modifying therapies. Current pharmacological treatments primarily alleviate symptoms and reduce exacerbations, but have limited ability to prevent progressive lung destruction or promote tissue repair. Increasing evidence indicates that beyond the classical cardiovascular functions of the renin-angiotensin system (RAS), it additionally plays a central role in regulating pulmonary inflammation, oxidative stress, extracellular matrix remodelling, cellular senescence and endogenous repair mechanisms. Experimental studies have shown that both pharmacological inhibition of the ACE/Ang II/AT1 axis and activation of the protective AT2 receptor and ACE2/Ang-(1-7)/Mas pathways attenuate multiple pathological processes involved in COPD progression. In this review, we comprehensively discuss the current preclinical evidence supporting pharmacological manipulation of the RAS in experimental models of pulmonary emphysema, highlighting the anti-inflammatory, antioxidant, anti-fibrotic, pro-resolutive and regenerative mechanisms associated with these therapeutic strategies. We further discuss emerging evidence indicating that activation of protective RAS pathways not only suppresses inflammation, but also promotes tissue repair through modulating autophagy, inflammasome activation, cellular senescence and endogenous regenerative signalling. These findings collectively position protective RAS modulation as a promising disease-modifying strategy for COPD and provide a strong rationale for future translational and clinical studies aimed at restoring pulmonary homeostasis.