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Acute respiratory distress syndrome (ARDS) is characterized by acute hypoxemia with diffuse alveolar damage and increased pulmonary microvascular permeability. Honokiol (HKL), the principal active ingredient of Chinese herb magnolia officinalis, protected the lung of experimental ARDS models via attenuation of inflammation and oxidative stress. However, whether HKL has protective effects against the dysfunction of pulmonary microvascular endothelial barrier and the potential mechanisms remain unclear.In the present study, we examined the levels of plasma Angiopoietin-2 (Ang-2) in ARDS patients, explored the effects of HKL on the vascular endothelial barrier at the ARDS animal and cell levels.Our data showed that compared with the healthy controls, circulating Ang-2 level was higher in the patients with ARDS, and were usually supposed to be positively related to the severity of ARDS. Moreover, HKL effectively inhibited lung inflammatory injury and microvascular leakage, and improved ARDS mice survival. HKL also inhibited the expression of Ang-2, ICAM-1 and VCAM-1, and restored the expression of Sirt3, β-Catenin and VE-Cadherin. Furthermore, HKL improved ECs survival and inhibited the apoptosis of ECs. The inhibition of Ang-2 expression in vitro by HKL is accompanied by the upregulation of Sirt3 and AMPK phosphorylation.Our data demonstrated that HKL protected pulmonary microvascular endothelial barrier against LPS-induced ARDS at least in part through activating the Sirt3/AMPK signaling and inhibiting the Ang-2 expression. Thus, our findings show that the activation of Sirt3 signaling is a potential mechanism for the protective effects of HKL on vascular barrier.