TY  - INPR
SN  - 1073-449X
KW  - Alveolar Epithelium
KW  -  Congenital Diaphragmatic Hernia
KW  -  Mechanical Compression
KW  -  Nanoparticles
KW  -  VEGF
A1  - Loukogeorgakis, Stavros P
A1  - Michielin, Federica
A1  - Al-Juffali, Noura
A1  - Jimenez, Julio
A1  - Shibuya, Soichi
A1  - Allen-Hyttinen, Jessica
A1  - Eastwood, Mary Patrice
A1  - Alhendi, Ahmed SN
A1  - Davidson, Joseph
A1  - Naldi, Eleonora
A1  - Maghsoudlou, Panagiotis
A1  - Tedeschi, Alfonso
A1  - Khalaf, Sahira
A1  - Platé, Manuela
A1  - Fachin, Camila
A1  - Dos Santos Dias, Andre
A1  - Sindhwani, Nikhil
A1  - Scaglioni, Dominic
A1  - Xenakis, Theodoros
A1  - Sebire, Neil
A1  - Giomo, Monica
A1  - Eaton, Simon
A1  - Toelen, Jaan
A1  - Luni, Camilla
A1  - Pavan, Piero
A1  - Carmeliet, Peter
A1  - Russo, Francesca
A1  - Janes, Samuel
A1  - Nikolic, Marko Z
A1  - Elvassore, Nicola
A1  - Deprest, Jan
A1  - De Coppi, Paolo
AV  - public
ID  - discovery10205062
JF  - American Journal of Respiratory and Critical Care Medicine
N1  - This version is the author accepted manuscript. For information on re-use, please refer to the publisher?s terms and conditions. - For the purpose of open access, the author has applied a CC BY public copyright license to any author
accepted manuscript version arising from this submission.
TI  - Prenatal VEGF Nano-Delivery Reverses Congenital Diaphragmatic Hernia-associated Pulmonary Abnormalities
PB  - American Thoracic Society
N2  - RATIONALE: Congenital diaphragmatic hernia (CDH) results in lung hypoplasia. In severe cases, tracheal occlusion (TO) can be offered to promote lung growth. However the benefit is limited, and novel treatments are required to supplement TO. Vascular endothelial growth factor (VEGF) is downregulated in animal models of CDH and could be a therapeutic target, but its role in human CDH is not known. OBJECTIVES: To investigate whether VEGF supplementation could be a suitable treatment for CDH-associated lung pathology. METHODS: Fetal lungs from CDH patients were used to determine pulmonary morphology and VEGF expression. A novel human ex vivo model of fetal lung compression recapitulating CDH features was developed and used to determine the effect of exogenous VEGF supplementation. A nanoparticle-based approach for intra-pulmonary delivery of VEGF was developed by conjugating it on functionalized nanodiamonds (ND-VEGF) and was tested in experimental CDH in vivo. MEASUREMENTS AND MAIN RESULTS: VEGF expression was downregulated in distal pulmonary epithelium of human CDH fetuses in conjunction with attenuated cell proliferation. The compression model resulted in impaired branching morphogenesis similar to CDH and downregulation of VEGF expression in conjunction with reduced proliferation of terminal bud epithelial progenitors; these could be reversed by exogenous supplementation of VEGF. Prenatal delivery of VEGF with the ND-VEGF platform in CDH fetal rats resulted in lung growth and pulmonary arterial remodelling that was complementary to that achieved by TO alone with appearances comparable to healthy controls. CONCLUSIONS: This innovative approach could have a significant impact on the treatment of CDH.
UR  - https://doi.org/10.1164/rccm.202401-0161oc
Y1  - 2025/02/13/
ER  -