title: Ca(2+)-activated K(+) channel-3.1 blocker TRAM-34 attenuates airway remodeling and eosinophilia in a murine asthma model.
abstract: Key features of asthma include bronchial hyperresponsiveness (BHR), eosinophilic airway inflammation, and bronchial remodeling, characterized by subepithelial collagen deposition, airway fibrosis, and increased bronchial smooth muscle (BSM) mass. The calcium-activated K(+) channel K(Ca)3.1 is expressed by many cells implicated in the pathogenesis of asthma, and is involved in both inflammatory and remodeling responses in a number of tissues. The specific K(Ca)3.1 blocker 5-[(2-chlorophenyl)(diphenyl)methyl]-1H-pyrazole (TRAM-34) attenuates BSM cell proliferation, and both mast cell and fibrocyte recruitment in vitro. We aimed to examine the effects of K(Ca)3.1 blockade on BSM remodeling, airway inflammation, and BHR in a murine model of chronic asthma. BALB/c mice were sensitized with intraperitoneal ovalbumin (OVA) on Days 0 and 14, and then challenged with intranasal OVA during Days 14-75. OVA-sensitized/challenged mice received TRAM-34 (120 mg/kg/day, subcutaneous) from Days -7 to 75 (combined treatment), Days -7 to 20 (preventive treatment), or Days 21 to 75 (curative treatment). Untreated mice received daily injections of vehicle (n = 8 per group). Bronchial remodeling was assessed by histological and immunohistochemical analyses. Inflammation was evaluated using bronchoalveolar lavage and flow cytometry. We also determined BHR in both conscious and anesthetized mice via plethysmography. We demonstrated that curative treatment with TRAM-34 abolishes BSM remodeling and subbasement collagen deposition, and attenuates airway eosinophilia. Although curative treatment alone did not significantly reduce BHR, the combined treatment attenuated nonspecific BHR to methacholine. This study indicates that K(Ca)3.1 blockade could provide a new therapeutic strategy in asthma.
authors.affiliation: Centre de Recherche Cardio-Thoracique de Bordeaux, U1045, U1034, De´partement de Pharmacologie, CIC 0005, University of Bordeaux, Bordeaux, France.
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Girodet
authors.forename: Annaig
authors.initials: A
authors.lastname: Ozier
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Carvalho
authors.forename: Olga
authors.initials: O
authors.lastname: Ilina
authors.forename: Olga
authors.initials: O
authors.lastname: Ousova
authors.forename: Alain-Pierre
authors.initials: AP
authors.lastname: Gadeau
authors.forename: Hugues
authors.initials: H
authors.lastname: Begueret
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.forename: Roger
authors.initials: R
authors.lastname: Marthan
authors.forename: Peter
authors.initials: P
authors.lastname: Bradding
authors.forename: Patrick
authors.initials: P
authors.lastname: Berger
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects*; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D004802:Eosinophilia / Q000517:prevention & control*; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D024681:Potassium Channels, Calcium-Activated; D011720:Pyrazoles; C411671:TRAM 34