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Reconstructing the Emphysematous Lung – A Critical Appraisal and Case Study with VCU-CDSO3

Sakagami M, Li H, Truong TM, Hayashi K, Desai UR, Voelkel NF.

Respiratory Drug Delivery 2016. Volume 1, 2016: 13-22.

Abstract:

Emphysema progressively destroys lung’s alveolar structures and eventually causes death, yet no drug can repair its damages for a cure. A new pathobiologic hypothesis has thus been proposed, focused on the imbalanced lung cell proliferation and death due to reduced hypoxia-inducible factor-1α (HIF1α) and vascular endothelial growth factor (VEGF). Hence, we developed VCU-CDSO3, a novel lignin-like sulfated oligomer of caffeic acid, as a lipophilic Fe²⁺ chelator and an inhibitor of HIF1α degradation, to reverse this imbalance through its Fe²⁺ chelation-based restoration of HIF1α-VEGF axis in the lungs. CDSO3 indeed elevated HIF1α and VEGF levels, thereby stimulating lung cell proliferation and inhibiting emphysematous cell death in vitro. In rat models of established emphysema, two week pulmonary delivery of CDSO3 at 60 µg/kg repaired lung damages, enabling: 1) a 42-73% reversal in exercise endurance impairment and airspace enlargement; 2) a two-fold stimulation of a lung cell proliferation marker, PCNA; and 3) normalization of lung’s induced apoptotic caspase-3 and reduced HIF1α and VEGF levels. Excess Fe²⁺ and HIF1α inhibitors (2-methoxyestradiol or echinomycin) blocked the lung repair in vivo and the cell proliferative stimulation and anti-cell death activities in vitro. Hence, CDSO3 is a novel inhaled drug candidate that has been shown to repair lung damages and reverse emphysema in animal models by restoring lung cell proliferation and death balance via Fe²⁺ chelation-based modulation of the pathobiologic “HIF1α/VEGF deficiency.” Further work will be, however, necessary for its development toward patient use.