We have analyzed the effect of the
soluble guanylate cyclase (sGC) stimulator
BAY 41-2272 in a therapeutic intervention in guinea pigs chronically exposed to cigarette
smoke (CS). The effects of sGC stimulation on respiratory function, pulmonary hemodynamics, airspace size, vessel remodeling, and inflammatory cell recruitment to the lungs were evaluated in animals that had been exposed to CS for 3 mo. CS exposure was continued for an additional 3 mo in half of the animals and withdrawn in the other half. Animals that stopped CS exposure had slightly lower pulmonary artery pressure (PAP) and right ventricle (RV)
hypertrophy than those who continued CS exposure, but they did not recover from the
emphysema and the inflammatory cell infiltrate. Conversely, oral
BAY 41-2272 administration stopped progression or even reversed the CS-induced
emphysema in both current and former smokers, respectively. Furthermore,
BAY 41-2272 produced a reduction in the RV
hypertrophy, which correlated with a decrease in the PAP values. By contrast, the degree of vessel remodeling induced by CS remained unchanged in the treated animals. Functional network analysis suggested
perforin/
granzyme pathway downregulation as an action mechanism capable of stopping the progression of
emphysema after sGC stimulation. The pathway analysis also showed normalization of the expression of cGMP-dependent
serine/
kinases. In conclusion, in guinea pigs chronically exposed to CS, sGC stimulation exerts beneficial effects on the lung parenchyma and the pulmonary vasculature, suggesting that sGC stimulators might be a potential alternative for
chronic obstructive pulmonary disease treatment that deserves further evaluation.