Magnolol ameliorates lipopolysaccharide-induced acute lung injury in rats through PPAR-γ-dependent inhibition of NF-kB activation

doi:10.1016/j.intimp.2015.05.051

International Immunopharmacology

Volume 28, Issue 1, September 2015, Pages 270-278

https://doi.org/10.1016/j.intimp.2015.05.051 Get rights and content

Highlights

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Magnolol increases the PPAR-γ expression and activity in lungs instilled with LPS.
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Blocking PPAR-γ activity reverses the beneficial effects of magnolol in ALI.
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PPAR-γ involves magnolol-mediated suppression of NF-kB activation and inflammation.
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The protective effect of magnolol in LPS-induced ALI is mediated by PPAR-γ.

Abstract

Acute lung injury (ALI) has a high morbidity and mortality rate due to the serious inflammation and edema occurred in lung. Magnolol extracted from Magnolia officinalis, has been reported to exhibit anti-inflammatory, and antioxidant activities. Peroxisome proliferator-activated receptors (PPARs) are known to exert a cytoprotective effect against cellular inflammatory stress and oxidative injury. The aim of this study was to explore the involvement of PPAR-γ in the beneficial effect of magnolol in lipopolysaccharide (LPS)-induced ALI. We found that treatment with magnolol greatly improved the pathological features of ALI evidenced by reduction of lung edema, polymorphonuclear neutrophil infiltration, ROS production, the levels of pro-inflammatory cytokines in bronchoalveolar lavage fluid (BALF), the expression of iNOS and COX-2, and NF-κB activation in lungs exposed to LPS. Importantly, magnolol is capable of increasing the PPAR-γ expression and activity in lungs of ALI. However, blocking PPAR-γ activity with GW9662 markedly abolished the protective and anti-inflammatory effects of magnolol. Taken together, the present study provides a novel mechanism accounting for the protective effect of magnolol in LPS-induced ALI is at least partly attributed to induction of PPAR-γ in lungs, and in turn suppressing NF-κB-related inflammatory responses.

Introduction

Acute lung injury (ALI) is characterized by hypoxemia, pulmonary edema, and polymorphonuclear neutrophil (PMN) infiltration in lungs with a high morbidity and mortality in human [1]. Although the true mechanisms causing ALI remain unclear, it is generally accepted that the excessive inflammation in particular caused by bacterial infection plays a critical role in the development of ALI [2]. Lipopolysaccharide (LPS), a component of the cell walls of gram-negative bacteria, is a potent pathogen for inducing ALI through recruitment of inflammatory cells such as neutrophils and macrophages into lungs, resulting in release of several inflammatory mediators [3], [4]. Currently, intratracheal (i.t.) administration of LPS is widely used for induction of ALI animal model for its similar characteristics of human ALI. Thus, this model is suitable for investigating the pathogenesis and the therapeutic effects of potential drugs in ALI [5], [6].

Peroxisome proliferator-activated receptors (PPARs) belonging to ligand-activated transcription factors possess several biological functions such as regulation of lipid metabolism and glucose homeostasis [7]. When activated by their ligands, PPARs undergo a conformational change leading to recruitment of distinct coactivators and corepressors. Then, the PPAR complex combines with cis-retinoid X receptor (RXR) and translocates into the nucleus, where it regulates downstream gene transcription by binding to the peroxisome proliferator response element. There are three PPAR isoforms (PPAR-α, PPAR-β/δ, and PPAR-γ) existed in cells. Previous studies have indicated that PPAR-γ agonists are capable of inhibiting LPS-induced inflammatory responses in airway epithelial cells and neutrophilia, alveolar macrophages and ALI [8], [9], [10] by suppressing the release of pro-inflammatory cytokines and nuclear factor-κB (NF-κB) activation [11]. Therefore, compounds with activating PPAR-γ expression/activity may have a protective effect against inflammatory diseases such as ALI.

Magnolol (Fig. 1), a main bioactive ingredient of Magnolia officinalis, has board spectrum biological functions including anti-inflammatory activity, and attenuating endotoxin-induced multiple tissue damage and dysfunction [12], [13], which may be associated with inhibition of nuclear factor-kappa B (NF-κB)-mediated inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) expression and pro-inflammatory cytokine production [14]. However, whether magnolol has an ability to activate PPAR expression/activity and the involvement of PPARs in ALI remain unreported. The present study provides a new mechanism regarding the protective effect of magnolol in LPS-induced ALI that is likely to be mediated by PPAR-γ induction.

Section snippets

Materials and LPS-induced ALI model

Magnolol was purchased from Medical and Pharmaceutical Industry technology and Development Center (Taipei, Taiwan) with purity > 98%, and solubilized in DMSO and then diluted with normal saline as need and fixed the final concentration of DMSO at 1% (v/v). Other chemical agents used in the study were at least analytical grade. The experimental procedures of this study were conducted in accordance with the Guiding Principle in the Care and Use of Animals and approved by the Institutional Animal

Magnolol increased PPAR-γ expression and activation

Administration of magnolol dose-dependently increased PPAR-γ expression and activity (Fig. 1A and B) accompanied by a significant elevation of nuclear translocation of PPAR-γ (Fig. 1C), but did not affect other PPARs (PPAR-α and PPAR-β/δ) expression and activity (data not shown) in lungs challenged by LPS compared to control group. Moreover, there were no significant changes on PPAR-γ nuclear translocation, and activity (Fig. 1), as well as lung structure (Fig. 2A) in magnolol-treated alone

Discussion

The present study revealed that pretreatment with magnolol ameliorates the pathological symptoms and inflammatory responses in LPS-induced ALI. Importantly, we provide a novel mechanism that the protective effect of magnolol is mediated by PPAR-γ activation, because blocking PPAR-γ activity dramatically reversed the effects of magnolol. These findings highlight the potential use of magnolol for ALI treatment.

Just as previous studies [17], [18], intratracheal instillation of LPS resulted in an

Acknowledgment

This study was partly supported by a research grant from the National Science Council of Taiwan, Republic of China (NSC 97-2320-B-016-008-MY3).

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Magnolol ameliorates lipopolysaccharide-induced acute lung injury in rats through PPAR-γ-dependent inhibition of NF-kB activation

Highlights

Abstract

Introduction

Section snippets

Materials and LPS-induced ALI model

Magnolol increased PPAR-γ expression and activation

Discussion

Acknowledgment

Lancet

J. Ethnopharmacol.

Pharmacol. Res.

Pharmacol. Ther.

Eur. J. Pharmacol.

J. Ethnopharmacol.

J. Surg. Res.

Cytokine Growth Factor Rev.

Chin. J. Nat. Med.

Int. Immunopharmacol.

Pharmacol. Ther.

Arch. Oral Biol.

Mol. Cell

Acute lung injury review

Intern. Med.

Toll-like receptor and tumour necrosis factor dependent endotoxin-induced acute lung injury

Int. J. Exp. Pathol.

Acute lung injury: apoptosis and signaling mechanisms

Exp. Biol. Med.