Prevention of monocrotaline-induced pulmonary

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],
[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.