Inhibitory effects of edaravone, a free radical scavenger, on cytokine-induced hyperpermeability of human pulmonary microvascular endothelial cells

A comparison with dexamethasone and nitric oxide synthase inhibitor

Yukie Saito, Yousuke Fujii, Masato Yashiro, Mitsuru Tsuge, Nobuyuki Nosaka, Nobuko Yamashita, Mutsuko Yamada, Hirokazu Tsukahara, Tsuneo Morishima

Research output: Contribution to journalArticle

Abstract

Lung hyperpermeability affects the development of acute respiratory distress syndrome (ARDS), but therapeutic strategies for the control of microvascular permeability have not been established. We examined the effects of edaravone, dexamethasone, and N-monomethyl-L-arginine (L-NMMA) on permeability changes in human pulmonary microvascular endothelial cells (PMVEC) under a hypercytokinemic state. Human PMVEC were seeded in a Boyden chamber. After monolayer confluence was achieved, the culture media were replaced respectively by culture media containing edaravone, dexamethasone, and L-NMMA. After 24-h incubation, the monolayer was stimulated with tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Fluorescein-labeled dextran was added. Then the transhuman PMVEC leak was measured. Expressions of vascular endothelial-cadherin (VE-cadherin) and zonula occludens-1 protein (ZO-1) were evaluated using real-time quantitative polymerase chain reaction and immunofluorescence microscopy. The results showed that TNF-α + IL-1β markedly increased pulmonary microvascular permeability. Pretreatment with edaravone, dexamethasone, or L-NMMA attenuated the hyperpermeability and inhibited the cytokine-induced reduction of VE-cadherin expression on immunofluorescence staining. Edaravone and dexamethasone increased the expression of ZO-1 at both the mRNA and protein levels. Edaravone and dexamethasone inhibited the permeability changes of human PMVEC, at least partly through an enhancement of VE-cadherin. Collectively, these results suggest a potential therapeutic approach for intervention in patients with ARDS.

Original languageEnglish
Pages (from-to)279-290
Number of pages12
JournalActa Medica Okayama
Volume69
Issue number5
Publication statusPublished - 2015

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Free Radical Scavengers
Endothelial cells
Nitric Oxide Synthase
Dexamethasone
omega-N-Methylarginine
Endothelial Cells
Cytokines
Lung
Zonula Occludens-1 Protein
Interleukin-1
Adult Respiratory Distress Syndrome
Capillary Permeability
Culture Media
Monolayers
Tumor Necrosis Factor-alpha
Permeability
Polymerase chain reaction
Dextrans
Fluorescein
Arginine

Keywords

  • Edaravone
  • Permeability
  • Pulmonary microvascular endothelial cells
  • Vascular endothelial-cadherin
  • Zonula occludens-1 protein

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

@article{9de4f69f69a14e5c8d5ca288f560a587,
title = "Inhibitory effects of edaravone, a free radical scavenger, on cytokine-induced hyperpermeability of human pulmonary microvascular endothelial cells: A comparison with dexamethasone and nitric oxide synthase inhibitor",
abstract = "Lung hyperpermeability affects the development of acute respiratory distress syndrome (ARDS), but therapeutic strategies for the control of microvascular permeability have not been established. We examined the effects of edaravone, dexamethasone, and N-monomethyl-L-arginine (L-NMMA) on permeability changes in human pulmonary microvascular endothelial cells (PMVEC) under a hypercytokinemic state. Human PMVEC were seeded in a Boyden chamber. After monolayer confluence was achieved, the culture media were replaced respectively by culture media containing edaravone, dexamethasone, and L-NMMA. After 24-h incubation, the monolayer was stimulated with tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Fluorescein-labeled dextran was added. Then the transhuman PMVEC leak was measured. Expressions of vascular endothelial-cadherin (VE-cadherin) and zonula occludens-1 protein (ZO-1) were evaluated using real-time quantitative polymerase chain reaction and immunofluorescence microscopy. The results showed that TNF-α + IL-1β markedly increased pulmonary microvascular permeability. Pretreatment with edaravone, dexamethasone, or L-NMMA attenuated the hyperpermeability and inhibited the cytokine-induced reduction of VE-cadherin expression on immunofluorescence staining. Edaravone and dexamethasone increased the expression of ZO-1 at both the mRNA and protein levels. Edaravone and dexamethasone inhibited the permeability changes of human PMVEC, at least partly through an enhancement of VE-cadherin. Collectively, these results suggest a potential therapeutic approach for intervention in patients with ARDS.",
keywords = "Edaravone, Permeability, Pulmonary microvascular endothelial cells, Vascular endothelial-cadherin, Zonula occludens-1 protein",
author = "Yukie Saito and Yousuke Fujii and Masato Yashiro and Mitsuru Tsuge and Nobuyuki Nosaka and Nobuko Yamashita and Mutsuko Yamada and Hirokazu Tsukahara and Tsuneo Morishima",
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TY - JOUR

T1 - Inhibitory effects of edaravone, a free radical scavenger, on cytokine-induced hyperpermeability of human pulmonary microvascular endothelial cells

T2 - A comparison with dexamethasone and nitric oxide synthase inhibitor

AU - Saito, Yukie

AU - Fujii, Yousuke

AU - Yashiro, Masato

AU - Tsuge, Mitsuru

AU - Nosaka, Nobuyuki

AU - Yamashita, Nobuko

AU - Yamada, Mutsuko

AU - Tsukahara, Hirokazu

AU - Morishima, Tsuneo

PY - 2015

Y1 - 2015

N2 - Lung hyperpermeability affects the development of acute respiratory distress syndrome (ARDS), but therapeutic strategies for the control of microvascular permeability have not been established. We examined the effects of edaravone, dexamethasone, and N-monomethyl-L-arginine (L-NMMA) on permeability changes in human pulmonary microvascular endothelial cells (PMVEC) under a hypercytokinemic state. Human PMVEC were seeded in a Boyden chamber. After monolayer confluence was achieved, the culture media were replaced respectively by culture media containing edaravone, dexamethasone, and L-NMMA. After 24-h incubation, the monolayer was stimulated with tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Fluorescein-labeled dextran was added. Then the transhuman PMVEC leak was measured. Expressions of vascular endothelial-cadherin (VE-cadherin) and zonula occludens-1 protein (ZO-1) were evaluated using real-time quantitative polymerase chain reaction and immunofluorescence microscopy. The results showed that TNF-α + IL-1β markedly increased pulmonary microvascular permeability. Pretreatment with edaravone, dexamethasone, or L-NMMA attenuated the hyperpermeability and inhibited the cytokine-induced reduction of VE-cadherin expression on immunofluorescence staining. Edaravone and dexamethasone increased the expression of ZO-1 at both the mRNA and protein levels. Edaravone and dexamethasone inhibited the permeability changes of human PMVEC, at least partly through an enhancement of VE-cadherin. Collectively, these results suggest a potential therapeutic approach for intervention in patients with ARDS.

AB - Lung hyperpermeability affects the development of acute respiratory distress syndrome (ARDS), but therapeutic strategies for the control of microvascular permeability have not been established. We examined the effects of edaravone, dexamethasone, and N-monomethyl-L-arginine (L-NMMA) on permeability changes in human pulmonary microvascular endothelial cells (PMVEC) under a hypercytokinemic state. Human PMVEC were seeded in a Boyden chamber. After monolayer confluence was achieved, the culture media were replaced respectively by culture media containing edaravone, dexamethasone, and L-NMMA. After 24-h incubation, the monolayer was stimulated with tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Fluorescein-labeled dextran was added. Then the transhuman PMVEC leak was measured. Expressions of vascular endothelial-cadherin (VE-cadherin) and zonula occludens-1 protein (ZO-1) were evaluated using real-time quantitative polymerase chain reaction and immunofluorescence microscopy. The results showed that TNF-α + IL-1β markedly increased pulmonary microvascular permeability. Pretreatment with edaravone, dexamethasone, or L-NMMA attenuated the hyperpermeability and inhibited the cytokine-induced reduction of VE-cadherin expression on immunofluorescence staining. Edaravone and dexamethasone increased the expression of ZO-1 at both the mRNA and protein levels. Edaravone and dexamethasone inhibited the permeability changes of human PMVEC, at least partly through an enhancement of VE-cadherin. Collectively, these results suggest a potential therapeutic approach for intervention in patients with ARDS.

KW - Edaravone

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KW - Vascular endothelial-cadherin

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JO - Acta Medica Okayama

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