Obesity-associated reduction of miR-150-5p in extracellular vesicles promotes ventilator-induced lung injury by modulating the lysosomal degradation of VE-cadherin.

Abstract

Obese patient has a high risk of ventilator-induced lung injury (VILI) but its underlying mechanisms remain elusive. This study was designed to explore the role of circulating plasma extracellular vesicles (EVs) on the progression of VILI in the context of obesity. After high tidal volume mechanical ventilation, mice treated with plasma EVs from obese patients developed more severe lung damage than mice treated with plasma EVs from normal controls. miRNA sequencing of plasma EVs from obese patients revealed a significant downregulation of miR-150-5p compared to the others. miR-150-5p was found to target on XBP1s which subsequently regulated RAB7 as verified through dual-luciferase assays. This pathway promoted lysosomal degradation of vascular endothelial (VE)-cadherin, leading to an increased endothelial permeability. Obese mice showed an enhanced XBP1s/RAB7 expression, reduced VE-cadherin levels, and aggravated endothelial barrier damage and all of which intensified VILI. Administration of miR-150-5p agomir in obese mice mitigated VILI. Thus, this study highlights the low levels of miR-150-5p in EVs from obese patients modulated VILI severity via the XBP1s/RAB7 axis and the lysosomal degradation of VE-cadherin.