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PR1P Stabilizes VEGF and Upregulates its Signaling to Reduce Elastase Induced Murine Emphysema.

Emphysema is a progressive and fatal lung disease with no cure that is characterized by thinning, enlargement and destruction of alveoli leading to impaired gas exchange. Disease progression is due in part to dysregulation of Vascular Endothelial Growth Factor (VEGF) signaling in the lungs and increased lung cell apoptosis. Here we asked whether PR1P, a novel short peptide we designed that increases VEGF binding to endothelial cells, could be used to improve outcome in in-vitro and in-vivo models of emphysema. We used computer simulation and in-vitro and in-vivo studies to show that PR1P upregulated endogenous VEGF Receptor-2 signaling by binding VEGF and preventing its proteolytic degradation. In so doing, PR1P mitigated toxin induced lung cell apoptosis, including from cigarette smoke extract in-vitro and from LPS in-vivo in mice. Remarkably, inhaled PR1P led to significantly increased VEGF levels in murine lungs within 30 minutes that remained greater than two-fold above control 24h later. Finally, inhaled PR1P reduced acute lung injury in 4- and 21-day elastase induced murine emphysema models. Taken together, these results highlight the potential of PR1P as a novel therapeutic agent for the treatment of emphysema or other lung diseases characterized by VEGF signaling dysregulation.