Abstract

Rationale and Background: Impairment of vascular endothelial integrity is one of the hallmarks of acute lung injury, which underlies leukocyte infiltration and edema formation and contributes to organ dysfunction. The peroxisome proliferator-activated receptor delta (PPARδ) is a transcription factor regulating vascular endothelial cell (EC) function. Our previous study revealed that selective deletion of PPARδ in the endothelium worsens ischemic vascular injury, disrupts endothelial integrity, and exacerbates vascular inflammation in a mouse model of hindlimb ischemia. Methods and Results: In this study, we investigated whether PPARδ is protective for EC function in acute vascular injury and inflammation in the mouse lung. We performed lipopolysaccharide (LPS)-induced endotoxemia in the EC-selective PPARδ knockout mice (Ppard EC-KO ) and their wild-type littermates (Ppard EC-WT ). The mortality of Ppard EC-KO mice was higher after LPS injection. The survived Ppard EC-KO mice showed more severe lung vascular inflammation suggested by sustained leukocyte infiltration in the lung tissues and in the bronchoalveolar fluid, more pro-inflammatory cytokine production, and higher expression of EC activation markers CCL2, ICAM1, VCAM1, and E-selectin. In addition, the lung endothelium of LPS-treated Ppard EC-KO mice has degraded endothelial glycocalyx and discontinuous EC junctions, resulting in increased vascular leakage. In vitro experiments using human lung microvascular endothelial cells (HLMVECs) revealed that silencing PPARδ downregulated the expressions of ZO-1, claudin-5, and VE-cadherin, and altered their membrane distribution, leading to hyperpermeability of EC monolayer, at basal level and also in the presence of LPS or TNFα. Silencing of PPARδ also induces more activation of pro-inflammatory transcription factors including STAT1, IRF3, and IRF7. Conclusion: In summary, our study showed the protective role of endothelial PPARδ against endotoxemia-induced disruption of vascular barrier function and vascular inflammation in the lung endothelium. (Supported by Hong Kong Research Grant Council GRF 14107822 and 14105321)

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