Prevention of monocrotaline-induced pulmonary vascular and myocardial remodeling by the selective neutrophil elastase inhibitor BAY 85-8501

Excess of neutrophil elastase activity has been implicated in the pathogenesis of pulmonary arterial hypertension (PAH). Neutrophil elastase acts as a mediator of tissue remodeling by degradation of extracellular matrix (ECM) structures, the release of growth factors, and increased deposition of ECM proteins such as tenascin-C, which amplify the proliferative response to growth factors. We therefore investigated the novel selective neutrophil elastase inhibitor BAY 85-8501 in a rat model of PAH. Four weeks after a single subcutaneous injection of monocrotaline (MCT), rats displayed severely elevated right ventricular (RV) systolic pressure and marked RV hypertrophy and dysfunction with a concomitant increase in RV remodeling (e.g tenascin-C, Osteopontin) markers. Furthermore there was an increase in lung Osteopontin, TIMP-1 and IL-8 expression. Treatment with BAY 85-8501 from day 14-28 significantly reduced RV pressure and RV hypertrophy with an improvement of RV dysfunction. Furthermore, BAY 85-8501 significantly reduced lung as well as RV remodeling markers. Conclusion: MCT-induced PAH is linked to upregulation of enhancers of matrix production and endothelial and smooth muscle cell proliferation. Selective inhibition of neutrophil elastase by BAY 85-8501 significantly improves these biomarkers, indicating substantial anti-remodeling and anti-inflammatory effects.