Title: Prevention of monocrotaline-induced pulmonary vascular and myocardial remodeling by the selective neutrophil elastase inhibitor BAY 85-8501. Dr. Martina Delbeck, [email protected], Dr. Volkhart Li, [email protected], Dr. Franz von Nussbaum,[email protected], Dr. Daniel Meibom, [email protected], Dr. Stefan Golz,[email protected], Dr. Klemens Lustig, [email protected], Dr. Hubert Truebel,[email protected], MD1 and Prof. Dr Stefan Schaefer, [email protected], MD5. 1Cardiology Research, BAYER Pharma AG, Wuppertal, Germany; 2Lead Discovery, BAYER Pharma AG, Wuppertal, Germany; 3Medicinal Chemistry, BAYER Pharma AG, Wuppertal, Germany; 4Research Pharmacokinetics, BAYER Pharma AG, Wuppertal, Germany and 5Clinical Science, BAYER Pharma AG, Wuppertal, Germany. Body: 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 BA Y 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.
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