title: Targeted inhibition of KCa3.1 channel attenuates airway inflammation and remodeling in allergic asthma.
abstract: KCa3.1 has been suggested to be involved in regulating cell activation, proliferation, and migration in multiple cell types, including airway inflammatory and structural cells. However, the contributions of KCa3.1 to airway inflammation and remodeling and subsequent airway hyperresponsiveness (AHR) in allergic asthma remain to be explored. The main purpose of this study was to elucidate the roles of KCa3.1 and the potential therapeutic value of KCa3.1 blockers in chronic allergic asthma. Using real-time PCR, Western blotting, or immunohistochemical analyses, we explored the precise role of KCa3.1 in the bronchi of allergic mice and asthmatic human bronchial smooth muscle cells (BSMCs). We found that KCa3.1 mRNA and protein expression were elevated in the bronchi of allergic mice, and double labeling revealed that up-regulation occurred primarily in airway smooth muscle cells. Triarylmethane (TRAM)-34, a KCa3.1 blocker, dose-dependently inhibited the generation and maintenance of the ovalbumin-induced airway inflammation associated with increased Th2-type cytokines and decreased Th1-type cytokine, as well as subepithelial extracellular matrix deposition, goblet-cell hyperplasia, and AHR in a murine model of asthma. Moreover, the pharmacological blockade and gene silencing of KCa3.1, which was evidently elevated after mitogen stimulation, suppressed asthmatic human BSMC proliferation and migration, and arrested the cell cycle at the G0/G1 phase. In addition, the KCa3.1 activator 1-ethylbenzimidazolinone-induced membrane hyperpolarization and intracellular calcium increase in asthmatic human BSMCs were attenuated by TRAM-34. We demonstrate for the first time an important role for KCa3.1 in the pathogenesis of airway inflammation and remodeling in allergic asthma, and we suggest that KCa3.1 blockers may represent a promising therapeutic strategy for asthma.
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Yu
authors.forename: Jian-Rong
authors.initials: JR
authors.lastname: Xu
authors.forename: Yan-Xia
authors.initials: YX
authors.lastname: Wang
authors.forename: Guang-Ni
authors.initials: GN
authors.lastname: Xu
authors.forename: Zu-Peng
authors.initials: ZP
authors.lastname: Xu
authors.forename: Kai
authors.initials: K
authors.lastname: Yang
authors.forename: Da-Zheng
authors.initials: DZ
authors.lastname: Wu
authors.forename: Yong-Yao
authors.initials: YY
authors.lastname: Cui
authors.forename: Hong-Zhuan
authors.initials: HZ
authors.lastname: Chen
mesh_terms: D056151:Airway Remodeling; D000818:Animals; D001249:Asthma / Q000276:immunology / Q000473:pathology*; D015153:Blotting, Western; D001980:Bronchi / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology / Q000473:pathology*; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010047:Ovalbumin / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D018418:Th2 Cells / Q000276:immunology; D015854:Up-Regulation
chemical_list: D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496925:Kcnn4 protein, mouse; D011720:Pyrazoles; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C411671:TRAM 34; D010047:Ovalbumin