Local Lung HIF-1α and VEGF Activation to Reverse Emphysema by a Sulfated Caffeic Acid Dehydropolymer
Year: 2026
Type: article
Abstract: 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.
Source: Biology
Authors: Tien M. Truong, Meghan L. Thompson, Umesh R. Desai, Masahiro Sakagami
Institution: Virginia Commonwealth University
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,258
OpenAlex ID: W7148444608