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Hydroxytyrosol Attenuates LPS-Induced Acute Lung Injury in Mice by Regulating Autophagy and Sirtuin Expression

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Background: Recently, the effects of hydroxytyrosol on autophagy during acute lung injury (ALI) have drawn increasing attention.

Objective: We explored the underlying molecular mechanisms by which hydroxytyrosol exerts its anti-inflammatory effects in a murine model of ALI by up-regulating autophagy.

Methods: Male BALB/c mice, challenged with intranasal instillations of LPS, were treated with or without hydroxytyrosol (HT, 100 mg/kg, intragastrically) 1 h prior to LPS exposure. Twenty-four hours later, lung and bronchoalveolar lavage (BAL) fluid samples were obtained for the determination of lung wet to dry weight (W/D) ratios, protein leakage levels, and differential counts of inflammatory cells in BAL fluid. LPS-induced cytokine activity, inflammatory factor levels, sirtuin (SIRT1/3/6) expression, mitogenactivated protein kinase (MAPK) activation, and autophagy marker expression in ALImice were examined by western blotting and staining methods. Molecular docking between HT and SIRT and MAPK was studied with a Sybyl/Surflex module.

Results: LPS-stimulated SIRT inhibition, MAPK phosphorylation, and autophagy suppression were all notably abolished by HT administration. HT treatment significantly attenuated pulmonary edema and inflammatory cell infiltration into lung tissues, accompanied by decreased lung W/D ratios, protein concentrations, and inflammatory cell levels in BAL fluid. LPS driven release of inflammatory mediators, including TNF-α, IL-1β, IL-6, IL-10, and MCP-1, was strongly regulated by HT.

Conclusions: The protective effect of HT on lung inflammation in ALI mice may be attributed to the promotion of autophagy, which is likely associated with the activation of the SIRT/MAPK signaling pathway. Importantly, this study provides new insight into the molecular mechanisms of HT and its therapeutic potential in the treatment of acute respiratory distress syndrome.

Keywords: Hydroxytyrosol; acute lung injury; autophagy; lipopolysaccharide; respiratory distress syndrome; sirtuin

Document Type: Research Article

Publication date: February 1, 2017

This article was made available online on April 28, 2017 as a Fast Track article with title: "Hydroxytyrosol Attenuates LPS-Induced Acute Lung Injury in Mice by Regulating Autophagy and Sirtuin Expression".

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  • Current Molecular Medicine is an interdisciplinary journal focused on providing the readership with current and comprehensive reviews on fundamental molecular mechanisms of disease pathogenesis, the development of molecular-diagnosis and/or novel approaches to rational treatment. The reviews should be of significant interest to basic researchers and clinical investigators in molecular medicine. Periodically the journal will invite guest editors to devote an issue on a basic research area that shows promise to advance our understanding of the molecular mechanism(s) of a disease or has potential for clinical applications.
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