PR1P Stabilizes VEGF and Upregulates Its Signaling to Reduce Elastase-induced Murine Emphysema
| Autor: | James M Rice, Victoria H. Ko, Avner Adini, Mark Puder, Benjamin D. Matthews, Amy Pan, Ratnakar Potla, Hao Wu, Duy T. Dao, Lumeng J. Yu, Hong Chen, Selome Z Mitiku |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Vascular Endothelial Growth Factor A
Pulmonary and Respiratory Medicine Clinical Biochemistry Apoptosis Lung injury Mice chemistry.chemical_compound Downregulation and upregulation In vivo Smoke Animals Medicine Computer Simulation Lung Molecular Biology Original Research Mice Inbred C3H Pancreatic Elastase business.industry Elastase Endothelial Cells Cell Biology respiratory system Vascular Endothelial Growth Factor Receptor-2 In vitro Up-Regulation respiratory tract diseases Pulmonary Alveoli Vascular endothelial growth factor Disease Models Animal medicine.anatomical_structure Pulmonary Emphysema chemistry Cancer research Female Peptides business Signal Transduction |
| Zdroj: | Am J Respir Cell Mol Biol |
| ISSN: | 1535-4989 1044-1549 |
| Popis: | 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 VEGF (vascular endothelial growth factor) signaling in the lungs and increased lung-cell apoptosis. Here we asked whether PR1P (Prominin-1–derived peptide), 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 concentrations in murine lungs within 30 minutes that remained greater than twofold above that of control animals 24 hours 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. |
| Databáze: | OpenAIRE |
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