N-Methyl-D-aspartate Receptor Excessive Activation Inhibited Fetal Rat Lung Development<i>In Vivo</i>and<i>In Vitro</i>

Liao, Zhengbu; Zhou, Xiaocheng; Luo, Ziqiang; Huo, Huiyi; Wang, Mingjie; Yu, Xiao-He; Cao, Chuanding; Ding, Ying; Xiong, Zeng; Yue, Shaojie

doi:10.1155/2016/5843981

Cited by 9 publications

(8 citation statements)

References 43 publications

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“…In addition, we confirmed that the NMDAR blocker, memantine, reduces airway inflammation in mice with chronic obstructive pulmonary disease (44). It also plays an important role in other models of acute lung injury, pulmonary fibrosis (45) and intrauterine lung dysplasia (46,47). These findings suggest that endogenous glutamate and NMDAR activation may be involved in various types of acute lung injury, airway inflammation, asthma, and pulmonary fibrosis.…”

Section: Discussionsupporting

confidence: 71%

N-methyl-D-aspartate receptor blockers attenuate bleomycin-induced pulmonary fibrosis by inhibiting endogenous mesenchymal stem cells senescence

Huang¹,

Zhou²,

Li³

et al. 2022

Ann Transl Med

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Background: A large number of our previous studies showed that endogenous glutamate and N-methyl-D-aspartate receptor (NMDAR) activation may be involved in various types of acute lung injury, airway inflammation, asthma, and pulmonary fibrosis. In animal models, the transplantation of exogenous bone marrow mesenchymal stem cells (BM-MSCs) is the most promising treatment for idiopathic pulmonary fibrosis. However, there are limited reports on the status of endogenous BM-MSCs in the process of bleomycin-induced pulmonary fibrosis in animals. Methods:We constructed a mouse model of bleomycin-induced pulmonary fibrosis. In vitro, the senescence model of BM-MSCs was constructed with hydrogen peroxide and high concentration of N-methyl-D-aspartate (NDMA). The changes in aging-related indexes were detected by senescence associated beta-galactosidase (SA-β-gal) staining, western blot, flow cytometry and real time-PCR. The epithelial-mesenchymal transformation (EMT) changes of mouse lung epithelial cells (MLE-12) co-cultured with senescent BM-MSCs were detected by immunofluorescence and western blotting. Results:We observed that endogenous BM-MSCs senescence occurs during bleomycin-induced pulmonary fibrosis in mice, and the model group had a higher expression level of the NMDAR subunit than the control group. We observed a significant increase in NMDAR subunit expression in a hydrogen peroxide-induced senescent cell model in vitro. BM-MSCs showed senescence-related phenotype and cell cycle arrest after high concentration of NMDA treatment. At the same time, the expression levels of the classic Wingless and int-1 (Wnt) pathway protein β-cantenin and downstream cyclin D1 also changed. In the co-culture of aged BM-MSCs and MLE-12 cells, EMT can be promoted in MLE-12 cells, and MK-801 can partially antagonize the occurrence of EMT. The NMDAR antagonist can partially prevent the above phenomenon.Conclusions: High concentrations of NMDA can promote senescence of BM-MSCs. NMDAR blockers may inhibit endogenous BM-MSCs aging through the WNT signaling pathway, thereby reducing the effect of bleomycin-induced pulmonary fibrosis.

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Section: Discussionsupporting

confidence: 71%

N-methyl-D-aspartate receptor blockers attenuate bleomycin-induced pulmonary fibrosis by inhibiting endogenous mesenchymal stem cells senescence

Huang¹,

Zhou²,

Li³

et al. 2022

Ann Transl Med

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“…However, the mechanism underlying the effects of intrauterine hypoxia on lung development is still unclear. We (17,22) previously reported that intrauterine hypoxia can induce alveolar dysplasia in the fetus and after birth.…”

Section: Discussionmentioning

confidence: 97%

“…A major cause of glutamate excitotoxicity is activation of the NMDA subtype of glutamate receptor, which mediates Ca 2ϩ -dependent cell death (23). Previously, we (22) found that excessive activation of NMDARs was involved in impaired development of fetal lungs under hypoxia, while a moderate block of NMDA receptor reduced the inhibitory effect of intrauterine hypoxia on lung development. The results of our previous study also revealed NMDA receptor expression in MSCs extracted from mouse bone marrow (21).…”

Section: Discussionmentioning

confidence: 99%

“…However, excessive activation of N-methyl-D-aspartic acid receptor (NMDAR) by large amounts of glutamate can cause neuronal cell death and chronic disease (24,48). Our previous study (22) showed that NMDAR was involved in intrauterine hypoxiainduced BPD and that intrauterine hypoxia could increase the expression of NMDAR in the lungs. Additionally, we found that bleomycin stimulation increased the glutamate release from bone marrow MSCs, whereas NMDAR activation decreased the proliferation and antifibrotic function of bone marrow MSCs in a bleomycin-induced pulmonary fibrosis model (21).…”

Section: Introductionmentioning

confidence: 99%

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Excessive activation of NMDA receptor inhibits the protective effect of endogenous bone marrow mesenchymal stem cells on promoting alveolarization in bronchopulmonary dysplasia

Yue

Luo

Liao

et al. 2019

American Journal of Physiology-Cell Physiology

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We studied the role of bone marrow mesenchymal stem cells (MSCs) in our established model of bronchopulmonary dysplasia (BPD) induced by intrauterine hypoxia in the rat. First, we found that intrauterine hypoxia can reduce the number of MSCs in lungs and bone marrow of rat neonates, whereas the administration of granulocyte colony-stimulating factor or busulfan to either motivate or inhibit bone marrow MSCs to lungs altered lung development. Next, in vivo experiments, we confirmed that intrauterine hypoxia also impaired bone marrow MSC proliferation and decreased cell cycling activity. In vitro, by using the cultured bone marrow MSCs, the proliferation and the cell cycling activity of MSCs were also reduced when N-methyl-d-aspartic acid (NMDA) was used as an NMDA receptor (NMDAR) agonist. When MK-801 or memantine as NMDAR antagonists in vitro or in vivo was used, the reduction of cell cycling activity and proliferation were partially reversed. Furthermore, we found that intrauterine hypoxia could enhance the concentration of glutamate, an amino acid that can activate NMDAR, in the bone marrow of neonates. Finally, we confirmed that the increased concentration of TNF-ɑ in the bone marrow of neonatal rats after intrauterine hypoxia induced the release of glutamate and reduced the cell cycling activity of MSCs, and the latter could be partially reversed by MK-801. In summary, intrauterine hypoxia could decrease the number of bone marrow MSCs that could affect lung development and lung function through excessive activation of NMDAR that is partially caused by TNF-ɑ.

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“…An increasing body of evidence suggests the expression of functional NMDA receptors in the lungs and their critical role in glutamate induced acute lung injury and acute respiratory distress syndrome. 4,13,14,[17][18][19][20] Despite its direct role in lung injury, little effort has been taken to develop NMDA receptor based therapeutic strategies for the treatment of lung diseases. With the revolution in glutamate receptor pharmacology in the past decade that yielded a variety of chemical tools to modulate NMDA receptors, [31][32][33][34][35][36] and a COVID-19 pandemic that kills humans by primarily affecting lung function, this could be a suitable time to start working on a novel drug target for SARS treatment.…”

Section: Discussionmentioning

confidence: 99%

NMDA receptor modulation and severe acute respiratory syndrome treatment

Costa

2021

F1000Res

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N-Methyl-D-aspartate (NMDA) subtype of glutamate receptors is expressed in the human lungs and central nervous system. NMDA receptor potentiation could increase calcium ion influx and promote downstream signaling mechanisms associated with cellular contractions that are disrupted in severe acute respiratory syndrome. Pharmacological effects generated by triggering glutamate receptor function in the brain, coupled with concurrent stimulation of the respiratory tract, may produce a synergetic effect, improving the airway smooth muscle function. A novel multipronged intervention to simultaneously potentiate NMDA receptors expressed both in the central nervous system and airway muscles would be helpful for the treatment of severe acute respiratory syndrome that deteriorates peripheral and central nervous system function before causing death in humans.

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N-Methyl-D-aspartate Receptor Excessive Activation Inhibited Fetal Rat Lung DevelopmentIn VivoandIn Vitro

Cited by 9 publications

References 43 publications

N-methyl-D-aspartate receptor blockers attenuate bleomycin-induced pulmonary fibrosis by inhibiting endogenous mesenchymal stem cells senescence

N-methyl-D-aspartate receptor blockers attenuate bleomycin-induced pulmonary fibrosis by inhibiting endogenous mesenchymal stem cells senescence

Excessive activation of NMDA receptor inhibits the protective effect of endogenous bone marrow mesenchymal stem cells on promoting alveolarization in bronchopulmonary dysplasia

NMDA receptor modulation and severe acute respiratory syndrome treatment

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