Ebselen suppresses late airway responses and airway inflammation in guinea pigs.
Although ebselen, a seleno-organic compound, inhibits inflammation in various animal models, its efficacy as an anti-asthma drug remains to be clarified. In this study, we investigated the inhibitory effect of ebselen on a guinea pig asthma model. Ebselen was orally administered at dosages of 1-20 mg/kg 2 h before an ovalbumin (OA) challenge, and then airway responses, airway inflammation, the generation of superoxide, H(2)O(2), and nitrotyrosine, and the induction of inducible nitric oxide synthase (iNOS) were evaluated. Sensitized animals challenged with OA aerosol showed dual airflow limitations, i.e., immediate and late airway responses (IAR and LAR). Ebselen significantly inhibited LAR at dosages greater than 10 mg/kg, but did not inhibit IAR at any dosage. Bronchoalveolar lavage (BAL) examination showed that airway inflammation was significantly suppressed by ebselen at 10 mg/kg. The generation of superoxide and H(2)O(2) occurred on endothelial cells of LAR bronchi, and was inhibited by 10 mg/kg of ebselen. Superoxide generation was inhibited by diphenyleneiodonium chloride (DPI), a NAD(P)H oxidase inhibitor, but not by allopurinol, a xanthine oxidase inhibitor. Immunoreactivities for iNOS and nitrotyrosine were also observed on endothelial cells of LAR bronchi and were abolished in ebselen-treated animals. The present findings suggest that ebselen can be applied as a new therapeutic agent for asthma. The possible mechanisms by which ebselen inhibits LAR likely involve suppression of oxidant formation and iNOS induction in endothelial cells.
Zhang
Minjie
M
Department of Pulmonary Medicine, Institute of Clinical Medicine, University of Tsukuba, Tennoudai 1-1-1, Tsukuba, Ibaraki, Japan.
Nomura
Akihiro
A
Uchida
Yoshiyuki
Y
Iijima
Hiroaki
H
Sakamoto
Tohru
T
Iishii
Yukio
Y
Morishima
Yuko
Y
Mochizuki
Mie
M
Masuyama
Kuniko
K
Hirano
Kuniyoshi
K
Sekizawa
Kiyohisa
K
D000403:Airway Resistance / Q000187:drug effects*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000975:Antioxidants / Q000494:pharmacology*; D019540:Area Under Curve; D001249:Asthma / Q000188:drug therapy* / Q000473:pathology; D001393:Azoles / Q000494:pharmacology*; D001991:Bronchitis / Q000188:drug therapy* / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D003520:Cyclophosphamide / Q000008:administration & dosage; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D004789:Enzyme Activation; D005260:Female; D006168:Guinea Pigs; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007124:Immunoenzyme Techniques; D054833:Isoindoles; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D016566:Organoselenium Compounds / Q000494:pharmacology*; D010047:Ovalbumin / Q000008:administration & dosage; D010446:Peptide Fragments / Q000276:immunology; D011817:Rabbits; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012129:Respiratory Function Tests; D012130:Respiratory Hypersensitivity / Q000188:drug therapy*; D013481:Superoxides / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D018906:Antineoplastic Agents, Alkylating; D000975:Antioxidants; D001393:Azoles; D054833:Isoindoles; D016566:Organoselenium Compounds; D010446:Peptide Fragments; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D013481:Superoxides; C002744:3-nitrotyrosine; C042986:ebselen; D014443:Tyrosine; D003520:Cyclophosphamide; D010047:Ovalbumin; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II