NMDA Receptor Antagonist Attenuates Bleomycin-Induced Acute Lung Injury.

Yang Li,Dandan Feng,Lian Li,Wei Liu,Shao Jie Yue,Xiaoting Huang,Qingmei Cheng,Yong Liu,Ziqiang Luo,Yanhong Huang,Feiyan Zhao,Siwei Luo,Jianzhong Han,Xiangping Peng,Bernhard Ryffel

doi:10.1371/journal.pone.0125873

Yang Li, Dandan Feng + Show 13 more

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https://doi.org/10.1371/journal.pone.0125873

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Abstract

BackgroundGlutamate is a major neurotransmitter in the central nervous system (CNS). Large amount of glutamate can overstimulate N-methyl-D-aspartate receptor (NMDAR), causing neuronal injury and death. Recently, NMDAR has been reported to be found in the lungs. The aim of this study is to examine the effects of memantine, a NMDAR channel blocker, on bleomycin-induced lung injury mice.MethodsC57BL/6 mice were intratracheally injected with bleomycin (BLM) to induce lung injury. Mice were randomized to receive saline, memantine (Me), BLM, BLM plus Me. Lungs and BALF were harvested on day 3 or 7 for further evaluation.ResultsBLM caused leukocyte infiltration, pulmonary edema and increase in cytokines, and imposed significant oxidative stress (MDA as a marker) in lungs. Memantine significantly mitigated the oxidative stress, lung inflammatory response and acute lung injury caused by BLM. Moreover, activation of NMDAR enhances CD11b expression on neutrophils.ConclusionsMemantine mitigates oxidative stress, lung inflammatory response and acute lung injury in BLM challenged mice.

Highlights

The development and progression of many acute and chronic lung disorders are associated with excessive or unresolved inflammation, which can result in cell injury and other pathological consequences
In order to check if Glu was released after BLM challenge in lungs at Day 3, we used high performance liquid chromatography (HPLC) to determine the changes of 17 kinds of amino acid in bronchoalveolar lavage fluid (BALF)
Three days after BLM injured, only the concentration of Glu and Gly in BALF were higher in the BLM group than in the saline control group(Fig 1B, P

Summary

Introduction

The development and progression of many acute and chronic lung disorders are associated with excessive or unresolved inflammation, which can result in cell injury and other pathological consequences. Extracellular glutamate concentrations are increased by abnormal release and/or clearance. This causes overstimulation of glutamate receptors, resulting in neuronal injury or death, known as excitotoxicity [5]. Mononuclear leukocytes and neutrophils can release glutamate, which can further exacerbate blood brain-barrier-injury [12, 13]. Several lines of evidence indicate that NMDARs play an important role in regulating inflammation in neuronal and non-neuronal cells and tissues, such as chronic morphine-induced neuroinflammation, retinal damage, arthritis and cardiac inflammation [15, 17,18,19]. Large amount of glutamate can overstimulate N-methyl-D-aspartate receptor (NMDAR), causing neuronal injury and death. The aim of this study is to examine the effects of memantine, a NMDAR channel blocker, on bleomycininduced lung injury mice

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