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.
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 trans-human 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.
Department of Pediatrics, Okayama University Graduate School of Medicine,Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.yukiepr@yahoo.co.jp.
Yukie
Y
Saito
Yousuke
Y
Fujii
Masato
M
Yashiro
Mitsuru
M
Tsuge
Nobuyuki
N
Nosaka
Nobuko
N
Yamashita
Mutsuko
M
Yamada
Hirokazu
H
Tsukahara
Tsuneo
T
Morishima
D015703:Antigens, CD / Q000032:analysis; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015820:Cadherins / Q000032:analysis; D002199:Capillary Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology*; D000077553:Edaravone; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D062826:Zonula Occludens-1 Protein / Q000032:analysis; D019323:omega-N-Methylarginine / Q000494:pharmacology; D000099152:Cadherin 5
D015703:Antigens, CD; D000983:Antipyrine; D015820:Cadherins; D016207:Cytokines; D003907:Dexamethasone; D000077553:Edaravone; D016166:Free Radical Scavengers; D018799:Intercellular Adhesion Molecule-1; D019001:Nitric Oxide Synthase; D062826:Zonula Occludens-1 Protein; D019323:omega-N-Methylarginine; D000099152:Cadherin 5; C569042:TJP1 protein, human