Sulfated dehydropolymer of caffeic acid: In vitro anti-lung cell death activity and in vivo intervention in emphysema induced by VEGF receptor blockade

Publication date: Available online 23 June 2017 Source:Pulmonary Pharmacology & Therapeutics Author(s): Tien M. Truong, Hua Li, Sneha Dhapare, Umesh R. Desai, Nobert F. Voelkel, Masahiro Sakagami Induced lung cell death and impaired hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) signaling are proposed as a pathobiologic mechanism for alveolar structural destruction and loss in emphysema. We hypothesized that our sulfated dehydropolymer of caffeic acid, CDSO3, exerts anti-cell death activities and therapeutic interventions in emphysema by virtue of Fe2+ chelation-based HIF-1α/VEGF stabilization and elevation. The Fe2+ chelating activity was determined in the chromogenic ferrozine-Fe2+ chelation inhibitory assay. The in vitro anti-cell death activities and their Fe2+ and HIF-1α dependence were assessed against a range of emphysematous insults in the lung endothelial (HMVEC-L) and epithelial (A549) cells. CDSO3 was spray-dosed to the lung for three weeks (day 1–21) in an in vivo rat model of apoptotic emphysema induced with a VEGF receptor antagonist SU5416. Post-treatment treadmill exercise endurance, airspace enlargement, and several lung biomarkers/proteins were measured. CDSO3 was a potent Fe2+ chelating molecule. At 10 μM, CDSO3 inhibited HMVEC-L and A549 cell death induced by histone deacetylase inhibition with trichostatin A, VEGF receptor blockade with SU5416, and cigarette smoke extract by 65–99%, which were...
Source: Pulmonary Pharmacology and Therapeutics - Category: Respiratory Medicine Source Type: research