Protective Effects of Platycodin D on Lipopolysaccharide-Induced Acute Lung Injury by Activating LXRα-ABCA1 Signaling Pathway.

Xiaoyu Hu,Yunhe Fu,Xiaojie Lu,Naisheng Zhang,Yongguo Cao,Zecai Zhang,Wenlong Zhang

doi:10.3389/fimmu.2016.00644

Abstract

The purpose of this study was to investigate the protective effects of platycodin D (PLD) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and clarify the possible mechanism. An LPS-induced ALI model was used to confirm the anti-inflammatory activity of PLD in vivo. The A549 lung epithelial cells were used to investigate the molecular mechanism and targets of PLD in vitro. In vivo, the results showed that PLD significantly attenuated lung histopathologic changes, myeloperoxidase activity, and pro-inflammatory cytokines levels, including TNF-α, IL-1β, and IL-6. In vitro, PLD inhibited LPS-induced IL-6 and IL-8 production in LPS-stimulated A549 lung epithelial cells. Western blot analysis showed that PLD suppressed LPS-induced NF-κB and IRF3 activation. Moreover, PLD did not act though affecting the expression of TLR4. We also showed that PLD disrupted the formation of lipid rafts by depleting cholesterol and prevented LPS-induced TLR4 trafficking to lipid rafts, thereby blocking LPS-induced inflammatory response. Finally, PLD activated LXRα–ABCA1-dependent cholesterol efflux. Knockdown of LXRα abrogated the anti-inflammatory effects of PLD. The anti-inflammatory effects of PLD was associated with upregulation of the LXRα–ABCA1 pathway, which resulted in disrupting lipid rafts by depleting cholesterol and reducing translocation of TLR4 to lipid rafts.

Highlights

Acute lung injury (ALI) takes responsibility for significant morbidity and is associated with an up to 30–50% mortality rate [1]
To investigate the protective effects of platycodin D (PLD) on LPS-induced acute lung injury (ALI), lung pathologic changes were determined by hematoxylin and eosin (H&E) staining
Our results showed that PLD significantly attenuated LPS-induced lung damage

Summary

Introduction

Acute lung injury (ALI) takes responsibility for significant morbidity and is associated with an up to 30–50% mortality rate [1]. The epithelial cells played an important role in innate immune responses. It provides a physico-chemical barrier and responds to inhaled microorganisms by releasing inflammatory mediators [2]. Lipopolysaccharide (LPS) activates TLR4 signaling pathway and triggers an inflammatory response in ALI [3]. Activation of ABCA1 and ABCG1 could induce cholesterol efflux from plasma membrane microdomains known as lipid rafts [4]. Lipid rafts, enriched in cholesterol and sphingolipids, are microdomains of the plasma membrane. They serve as a platform for signal transduction and play an important role in TLR4 signal pathway [5]. Treatment with raft-disrupting drugs could suppress LPS-induced NF-κB activation and TNF-α production [6, 7]

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