Local Lung HIF-1α and VEGF Activation to Reverse Emphysema by a Sulfated Caffeic Acid Dehydropolymer

In emphysema, the alveolar septal structure is progressively destroyed, which is believed to be irreversible. However, as it has recently been linked to vascular endothelial growth factor (VEGF) deficiency, we hypothesized that VEGF stimulation can promote lung cell proliferation/migration to reverse emphysema. Our sulfated caffeic acid dehydropolymer, CDSO3, was thus examined in vitro and in vivo, given its VEGF-stimulating activity via ferrous ion (Fe²⁺) chelation-mediated stabilization of hypoxia-inducible factor-1α (HIF-1α). In lung epithelial/endothelial cells, CDSO3 promoted proliferation and wound closure by 1.6-3.0-fold at 10 μM; however, these effects were negated by excess FeSO₄ or an HIF-1α inhibitor, indicating an Fe²⁺- and HIF-1α-dependent mechanism. In rat models of established emphysema induced by cigarette smoke extract or the VEGF receptor antagonist SU5416, two-week lung administration of CDSO3 at 60 μg/kg from day 21 enabled: 68-79% recovery of exercise endurance and airspace enlargement/destruction; a 1.8-fold increase in proliferating cell nuclear antigen above healthy levels; normalization of cleaved caspase-3; restoration of HIF-1α; and a 1.3-fold increase in VEGF above healthy levels. In contrast, CDSO3 pre-chelated with Fe²⁺ was ineffective. In conclusion, Fe²⁺ chelation-mediated HIF-1α stabilization and VEGF stimulation via local lung delivery of CDSO3 can reverse established emphysema by promoting cell growth and survival.