Glucocorticoids ameliorate antigen-induced bronchial smooth muscle hyperresponsiveness by inhibiting upregulation of RhoA in rats.
To determine the mechanism(s) of the inhibitory effect of glucocorticoids on airway hyperresponsiveness in allergic bronchial asthma, the effects of systemic treatment with glucocorticoids on bronchial smooth muscle hyperresponsiveness and RhoA upregulation were investigated in rats with allergic bronchial asthma. Rats were sensitized and repeatedly challenged with 2,4-dinitrophenylated Ascaris suum antigen. Animals were also treated with prednisolone or beclomethasone (each 10 mg/kg, i.p.) once a day during the antigen inhalation period. Repeated antigen inhalation caused a marked bronchial smooth muscle hyperresponsiveness to acetylcholine with an upregulation of RhoA. Augmented acetylcholine-induced activation of RhoA and phosphorylation of myosin light chain were observed in bronchial smooth muscles of the antigen-exposed animals. Systemic treatment with either glucocorticoid used inhibited the bronchial smooth muscle hypercontraction until the level of the sensitized control rats that received saline inhalation instead of antigen challenge. Interestingly, both glucocorticoids also inhibited the upregulation of RhoA and augmented acetylcholine-induced activation of RhoA and phosphorylation of myosin light chain. In conclusion, glucocorticoids ameliorated the augmented bronchial smooth muscle contraction by inhibiting upregulation of RhoA. These effects of glucocorticoids may account for, in part, their beneficial effects in the treatment of asthma.
Chiba
Yoshihiko
Y
Department of Pharmacology, School of Pharmacy, Hoshi University, Shinagawa-ku, Tokyo, Japan. chiba@hoshi.ac.jp
Goto
Kumiko
K
Hirahara
Mayu
M
Sakai
Hiroyasu
H
Misawa
Miwa
M
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D000947:Antigens, Helminth; D017165:Ascaris suum / Q000276:immunology; D001249:Asthma / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D001507:Beclomethasone / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D009130:Muscle, Smooth / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation; D011239:Prednisolone / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D018927:Anti-Asthmatic Agents; D000947:Antigens, Helminth; D016085:Bronchoconstrictor Agents; D005938:Glucocorticoids; D018994:Myosin Light Chains; D011239:Prednisolone; D020742:rhoA GTP-Binding Protein; D001507:Beclomethasone; D000109:Acetylcholine