RT Journal Article
SR Electronic
T1 Caspase inhibition reduces severe pulmonary hypertension in the AdTGF-1β/SU5416 model of angioproliferative pulmonary hypertension and lung fibrosis
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP p3334
VO 38
IS Suppl 55
A1 Laszlo Farkas
A1 Daniela Farkas
A1 Donatas Kraskauskas
A1 Jack Gauldie
A1 Martin Kolb
A1 Norbert Voelkel
YR 2011
UL http://erj.ersjournals.com/content/38/Suppl_55/p3334.abstract
AB Pulmonary hypertension (PH) is associated with increased mortality in patients with idiopathic pulmonary fibrosis (IPF). The interaction between the fibrotic process and the pulmonary vasculature is incompletely understood.The current study aimed to investigate whether broad spectrum caspase inhibition can reduce severe angioproliferative PH in the combined model of AdTGF-β1 lung fibrosis and the VEGF receptor inhibitor SU5416.Female Sprague Dawley rats received AdTGF-β1 intratracheally at day 0, as well as one dose of SU5416 s.c. or CMC. Some AdTGF-β1/SU5416 animals received the caspase inhibitor Z-Asp-CH2-DCB or vehicle (DMSO) from day 6-28 At day 28, invasive pulmonary hemodynamics were assessed. The right lung was used for protein and RNA isolation, and the left lung was inflated with formalin and processed for histology.We detected clusters of VWF+ endothelial cells occluding the lumen of small pulmonary arteries in AdTGF-β1/SU5416, together with severe PH in AdTGF-β1/SU5416 rats vs. AdTGF-β1/CMC. At the same time, lung fibrosis was increased, as indicated by elevated mRNA expression of profibrotic and matrix genes. Western blots showed a significant increase in caspase-3 cleavage in AdTGF-β1/SU5416 rats. Treatment with Z-Asp-CH2-DCB reduced right ventricular systolic pressures by 19.4 mmHg in average in AdTGF-β1/SU5416 animals (P<0.05 vs. DMSO).In conclusion, our results indicate that angioproliferative pulmonary vasculopathy was induced in this new model, together with severe fibrosis, and that increased apoptosis contributes to both increased fibrosis and vascular pathology.