Lovastatin inhibits bronchial hyperresponsiveness by reducing RhoA signaling in rat allergic asthma.
Recent studies revealed an importance of a monomeric GTP-binding protein, RhoA, in contraction of bronchial smooth muscle (BSM). RhoA and its downstream have been proposed as a new target for the treatment of airway hyperresponsiveness in asthma. Statins are known to inhibit the functional activation of RhoA via the depletion of geranylgeranylpyrophosphate. To determine the beneficial effects of statins on the airway hyperresponsiveness in allergic bronchial asthma, we investigated the effects of systemic treatment with lovastatin on the augmented BSM contraction and activation of RhoA in rats with allergic bronchial asthma. Rats were sensitized and repeatedly challenged with 2,4-dinitrophenylated Ascaris suum antigen. Animals were also treated with lovastatin (4 mg kg(-1) day(-1) ip) once a day before and during the antigen inhalation period. Repeated antigen inhalation caused a marked BSM hyperresponsiveness to ACh with the increased expression and translocation of RhoA. Lovastatin treatments significantly attenuated both the augmented contraction and RhoA translocation to the plasma membrane. Lovastatin also reduced the increased cell number in bronchoalveolar lavage fluids and histological changes induced by antigen exposure, whereas the levels of immunoglobulin E in sera and interleukins-4, -6, and -13 in bronchoalveolar lavage fluids were not significantly changed. These findings suggest that lovastatin ameliorates antigen-induced BSM hyperresponsiveness, an important factor of airway hyperresponsiveness in allergic asthmatics, probably by reducing the RhoA-mediated signaling.
Chiba
Yoshihiko
Y
Department of Pharmacology, School of Pharmacy, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan. chiba@hoshi.ac.jp
Arima
Junko
J
Sakai
Hiroyasu
H
Misawa
Miwa
M
D000818:Animals; D000947:Antigens, Helminth / Q000009:adverse effects; D017165:Ascaris suum; D001249:Asthma / Q000209:etiology / Q000503:physiopathology*; D001886:Bordetella pertussis / Q000472:pathogenicity; D016535:Bronchial Hyperreactivity / Q000209:etiology / Q000503:physiopathology*; D004195:Disease Models, Animal; D007249:Inflammation / Q000503:physiopathology; D008148:Lovastatin / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D012137:Respiratory System / Q000187:drug effects / Q000503:physiopathology; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000502:physiology*
D000947:Antigens, Helminth; D008148:Lovastatin; D020742:rhoA GTP-Binding Protein