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Oxidized Phospholipid, 1-Palmitoyl-2-(9′-Oxo-Nonanoyl)-Glycerophosphocholine (PON-GPC), Produced in the Lung Due to Cigarette Smoking, Impairs Immune Function in Macrophages

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Abstract

Introduction

Pulmonary innate immunity is impaired in cigarette smokers, because the abundant oxidants present in cigarette smoke (CS) cause injury to lung cells. Pulmonary surfactant is a unique material that is important roles in reducing surface tension in the lung and defending against invading pathogens. Oxidants reportedly cleave surfactant phospholipids, resulting in the production of oxidized phospholipids, such as 1-palmitoyl-2-(9′-oxo-nonanoyl)-glycerophosphocholine (PON-GPC). Although oxidation of surfactant lipids is thought to be involved in the pathogenesis of smoking-related lung disease, there are no reports on the effect of oxidized surfactant lipid on the immune function of macrophages. We hypothesized that cigarette smoking elevates PON-GPC levels in the lung, and that PON-GPC impairs the innate immune function of macrophages.

Methods

The levels of PON-GPC in bronchoalveolar lavage fluid (BALF) recovered from mice exposed to CS for 2 weeks (n = 7) were measured by liquid chromatography with electrospray–ionization tandem mass spectrometry. The effects of PON-GPC on inducibility of tumor necrosis factor (TNF)-α, nitric oxide (NO), and nicotinamide adenine dinucleotide phosphate (NADP+) production, as well as bactericidal activity, were investigated in RAW264.7 cells or primary alveolar macrophages.

Results

The levels of PON-GPC in BALF of mice exposed to CS were significantly elevated, compared with those of control mice. PON-GPC attenuated TNF-α, NO, and NADP+ production in macrophages on stimulation with LPS plus IFN-γ. PON-GPC treatment attenuated the phosphorylation of p38 mitogen-activated protein kinase (MAPK). In addition, PON-GPC reduced the bactericidal activity of RAW264.7 cells.

Conclusions

CS may attenuate innate immunity in the lungs through oxidization of surfactant phospholipids.

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Abbreviations

AM:

Alveolar macrophage

BALF:

Bronchoalveolar lavage fluid

CS:

Cigarette smoke

DPPC:

Dipalmitoyl phosphatidylcholine

EDTA:

Ethylenediamine-N,N,N′,N′-tetraacetic acid

ELF:

Epithelial lining fluid

ERK:

Extracellular signal-regulated kinase

IFN:

Interferon

JNK:

Jun kinase

LC/MS/MS:

liquid chromatography with electrospray-ionization tandem mass spectrometry

LPS:

Lipopolysaccharide

MAPK:

Mitogen activated protein kinase

MOI:

Multiplicity of infection

NADP+ :

Nicotinamide adenine dinucleotide phosphate

NO:

Nitric oxide

Ox-PAPC:

1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine

PG-GPC:

1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine

PON-GPC:

1-palmitoyl-2-(9′-oxo-nonanoyl)-glycerophosphocholine

POV-GPC:

1-palmitoyl-2-(5′-oxo-valeroyl)-sn-glycero-3-phosphocholine

ROS:

Reactive oxygen species

STAT:

Signal transducer and activator of transcription

TLR4:

Toll-like receptor 4

TNF:

Tumor necrosis factor

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Acknowledgments

This study was supported by a grant-in-aid from the Global COE program of the Japan Society for the Promotion of Science and grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (18590835, 18790530, 19590880, and 20590892).

Conflict of interest

None of the authors have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

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Authors and Affiliations

  1. Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata, 990-9585, Japan

    Tomomi Kimura, Yoko Shibata, Keiko Yamauchi, Akira Igarashi, Sumito Inoue, Shuichi Abe & Isao Kubota

  2. Pharmacokinetic Research Laboratories, Kyowa Hakko Kirin Co. Ltd, Shizuoka, Japan

    Kazuhiro Fujita

  3. Fuji Plant, Kyowa Hakko Kirin Co. Ltd, Shizuoka, Japan

    Yoichi Uosaki

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  1. Tomomi Kimura
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Correspondence to Yoko Shibata.

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Kimura, T., Shibata, Y., Yamauchi, K. et al. Oxidized Phospholipid, 1-Palmitoyl-2-(9′-Oxo-Nonanoyl)-Glycerophosphocholine (PON-GPC), Produced in the Lung Due to Cigarette Smoking, Impairs Immune Function in Macrophages. Lung 190, 169–182 (2012). https://doi.org/10.1007/s00408-011-9331-2

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