The role of SIRT1 in LPS-induced lung endothelial barrier dysfunction and lung injury in vivo

Abstract

Introduction: It isn9t clear completely that the mechanism of the endothelial hyper-permeability in acute lung injury. Aims and objectives: The aim of this study was to determine the role of protein deacetylase SIRT1, one of the nicotinamide adenine dinucleotide(NAD+)-dependent intracellular silent information regulators, in lipopolysaccharide (LPS)-induced lung endothelial barrier dysfunction and lung injury in vivo. Methods: The cultured human pulmonary endothelial cells (HPECs) and mice were exposed to LPS, and were treated with SIRT1 activator SRT1720 or inhibitor EX527 after LPS exposure, respectively. The endothelial permeability was measured in transwell by use of FITC-dextra. Results: In cultured HPECs, LPS increased endothelial permeability in parallel with a decrease in SIRT1 expression. Consistent with this observation, SIRT1 activation with the potent sirt1 activator SRT1720 attenuated LPS-induced endothelial hyper-permeability in vitro, but increased by the SIRT1 inhibitor EX527. Intra-tracheal administration of LPS (5 mg/kg) in mice reduced sirts expression in lung tissue extracts, increased protein content and cell count in bronchial alveolar lavage fluid, and increased Evans Blue dye infiltration into the lung. Pretreatment with SRT1720 reduced the lung injury in LPS-treated WT mice, and EX527 accentuated the lung injury. Conclusions: We concluded that SIRT1 play a role in LPS-induced endothelial barrier dysfunction and that its activation attenuated the endothelial barrier dysfunction and lung injury.