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FASEB J. 2016 Mar;30(3):1317-27. doi: 10.1096/fj.15-275024. Epub 2015 Dec 11.

An endothelial TLR4-VEGFR2 pathway mediates lung protection against oxidant-induced injury.

Author information

1
*Section of Pulmonary, Critical Care, and Sleep Medicine, and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA; and Veterans Affairs Connecticut Healthcare System, New Haven, Connecticut, USA seyedtaghi.takyar@yale.edu patty.lee@yale.edu.
2
*Section of Pulmonary, Critical Care, and Sleep Medicine, and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA; and Veterans Affairs Connecticut Healthcare System, New Haven, Connecticut, USA.

Abstract

TLR4 deficiency causes hypersusceptibility to oxidant-induced injury. We investigated the role of TLR4 in lung protection, using used bone marrow chimeras; cell-specific transgenic modeling; and lentiviral delivery in vivo to knock down or express TLR4 in various lung compartments; and lung-specific VEGF transgenic mice to investigate the effect of TLR4 on VEGF-mediated protection. C57/BL6 mice were exposed to 100% oxygen in an enclosed chamber and assessed for survival and lung injury. Primary endothelial cells were stimulated with recombinant VEGF and exposed to hyperoxia or hydrogen peroxide. Endothelium-specific expression of human TLR4 (as opposed to its expression in epithelium or immune cells) increased the survival of TLR4-deficent mice in hyperoxia by 24 h and decreased LDH release and lung cell apoptosis after 72 h of exposure by 30%. TLR4 expression was necessary and sufficient for the protective effect of VEGF in the lungs and in primary endothelial cells in culture. TLR4 knockdown inhibited VEGF signaling through VEGF receptor 2 (VEGFR2), Akt, and ERK pathways in lungs and primary endothelial cells and decreased the availability of VEGFR2 at the cell surface. These findings demonstrate a novel mechanism through which TLR4, an innate pattern receptor, interacts with an endothelial survival pathway.

KEYWORDS:

HALI; TLR4; VEGF; lung injury

PMID:
26655705
PMCID:
PMC4750407
[Available on 2017-03-01]
DOI:
10.1096/fj.15-275024
[Indexed for MEDLINE]
Free PMC Article

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