Differential modulation of the sGC–cGMP pathway by sGC stimulators and activators in human lung cells

Chronic lung diseases are characterized by oxidative stress, inflammation, and fibroproliferation, conditions that impair nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic GMP (cGMP) signaling. Here, we investigated the differential effects of an sGC stimulator (riociguat) and an sGC activator (cinaciguat), alone or combined with the PDE5 inhibitor sildenafil, in primary human pulmonary cells exposed to cigarette smoke extract (CSE). Lung tissue from COPD and asthma patients displayed reduced sGC α1 and β1 expression, and CSE induced concentration-dependent oxidation of the sGC heme group, diminishing responsiveness to NO and to riociguat. Cinaciguat, but not riociguat, maintained cGMP production under oxidizing conditions, while co-treatment with sildenafil further increased cGMP levels for both drugs. In epithelial cells, fibroblasts, neutrophils, and endothelial monolayers, cinaciguat and riociguat attenuated CSE-induced oxidative stress, inflammatory cell adhesion, and profibrotic gene expression, with cinaciguat-particularly in combination with sildenafil-showing more robust effects across endpoints. These findings identify distinct pharmacodynamic profiles for sGC stimulators versus activators under oxidative conditions and support sGC modulation as a potential therapeutic approach in oxidative chronic lung diseases.