RhoA, a possible target for treatment of airway hyperresponsiveness in bronchial asthma.
Airway hyperresponsiveness to nonspecific stimuli is one of the characteristic features of allergic bronchial asthma. An elevated contractility of bronchial smooth muscle has been considered as one of the causes of the airway hyperresponsiveness. The contraction of smooth muscles including airway smooth muscles is mediated by both Ca²+-dependent and Ca²+-independent pathways. The latter Ca²+-independent pathway, termed Ca²+ sensitization, is mainly regulated by a monomeric GTP-binding protein, RhoA, and its downstream target Rho-kinase. In animal models of allergic bronchial asthma, an augmented agonist-induced, RhoA-mediated contraction of bronchial smooth muscle has been suggested. The RhoA/Rho-kinase signaling is now proposed as a novel target for the treatment of airway hyperresponsiveness in asthma. Herein, we will discuss the mechanism of development of bronchial smooth muscle hyperresponsiveness, one of the causes of the airway hyperresponsiveness, based on the recent studies using animal models of allergic bronchial asthma and/or cultured airway smooth muscle cells. The possibility of RhoA as a therapeutic target in asthma, especially airway hyperresponsiveness, will also be described.
Chiba
Yoshihiko
Y
Department of Pharmacology, School of Pharmacy, Hoshi University, Japan. chiba@hoshi.ac.jp
Matsusue
Kimihiko
K
Misawa
Miwa
M
D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism*; D001980:Bronchi / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000503:physiopathology*; D051381:Rats; D012137:Respiratory System / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction; D015533:Transcriptional Activation; D015854:Up-Regulation; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D002118:Calcium