Selective inhibition of neutrophil elastase by BAY 85-8501 improves exercise capacity and pulmonary hypertension in a porcine pancreatic elastase-induced emphysema model

Neutrophil elastase is a serine proteinase, that has the ability to degrade a wide range of matrix proteins, especially elastin, and plays an important role for the modulation of the inflammatory response. Uninhibited neutrophil elastase activity has been implicated in the development of emphysema and pulmonary vascular remodeling. We therefore investigated the novel selective neutrophil elastase inhibitor BAY 85-8501 in a porcine pancreatic elastase (pPE)-induced emphysema model in mice. After a single orotracheal administration of pPE (0.3 U), male C57Bl6J mice displayed a reduced exercise capacity (running distance, top speed) during the following three weeks. At day 21 hemodynamic and morphological investigations showed an elevated right ventricular systolic pressure and right ventricular hypertrophy. Treatment with BAY 85-8501 significantly reduced right ventricular pressure and right ventricular hypertrophy. This was associated with a significant larger running distance and higher top speed in comparison to the placebo group. Conclusion: The orotracheal application of porcine pancreatic elastase in mice induces tissue damage and inflammation, leading to pulmonary hypertension associated with emphysema. Selective inhibition of neutrophil elastase by BAY 85-8501 significantly increases exercise capacity and substantially improves hemodynamic and morphological parameters.