Paneghetti, L; (2015) Characterisation of a novel endogenous anti-inflammatory activity from endothelial cells and its translational application in pathology. Doctoral thesis , UCL (University College London).

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Abstract

Endothelial injury often causes intimal hyperplasia, a disease characterised by local inflammation and critical narrowing or restenosis of the blood vessel. Endothelial cells (EC) grown on collagen particles are highly effective in inhibiting intimal hyperplasia in various animal models, and this effect appears to be, at least in part, the result of EC-derived soluble factors that suppress local vascular inflammation. To test this hypothesis, we produced EC on collagen particles-conditioned medium (ECPCM), which was expected to contain soluble anti-inflammatory factors. Indeed, EC treated in vitro with ECPCM together with pro-inflammatory cytokines including tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) displayed reduced gene expression of the inflammation-related adhesion molecules E-selectin and VCAM-1. Investigation of the molecular mechanism of action for the anti-inflammatory activity excluded mRNA stability of E-selectin and VCAM-1, activation of signalling cascades via the NF-kB and Stat3 pathways, and nuclear localization of transcription factors. ECPCM did affect the TNFα-induced binding of p65, a subunit of the NF-kB transcription factor, to the E-selectin and VCAM-1 promoters. These results suggest that inhibition of gene transcription is responsible for the ECPCM-mediated suppression of inflammatory responses in EC. The therapeutic effects of ECPCM were supported by in vivo experiments performed on the mutant mouse strain JR5558, which develops spontaneous choroidal neovascularization (CNV) lesions associated with inflammatory cell recruitment and expression of inflammatory adhesion molecules. The CNV lesion area and recruitment of activated macrophages were both decreased in JR5558 mice given intraperitoneal injections of ECPCM. ECPCM might therefore have therapeutic potential in treating inflammatory vascular diseases.

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