The balance between classical and alternative renin–angiotensin system in ARDS: a narrative review

Acute respiratory distress syndrome (ARDS) is a complex inflammatory condition often requiring admission to intensive care. The renin–angiotensin system (RAS) has emerged as a key modulator of lung inflammation, vascular tone, permeability and pulmonary fibrosis in ARDS. Its effect depend on the activated biochemical pathway during the course of the disease: the classical Angiotensin-Converting Enzyme (ACE)/Angiotensin II/AT1R pathway exerts pro-inflammatory, vasoconstrictive and profibrotic effects, whereas the alternative ACE2/Angiotensin 1–7/MasR axis is associated with anti-inflammatory, vasodilatory and antifibrotic properties. Therapeutic research has largely focused on enhancing the alternative RAS to attenuate inflammation and fibrosis; however, emerging evidence suggests that activation of the classical RAS through exogenous angiotensin II administration may provide clinical benefit in selected etiologies of ARDS, potentially by improving systemic hemodynamic stability and modulating pulmonary vascular resistances. This interplay between the two RAS axes underscores the complexity of their role in ARDS pathophysiology and raises the possibility that selective, stage-dependent modulation of both pathways may represent a new therapeutic approach in this context. This narrative review examines the dual influence of RAS pathways in ARDS and explores the potential for targeted therapeutic interventions at different disease stages.