Ca2+-activated K+ channel-3.1 blocker TRAM-34 attenuates airway remodeling and eosinophilia in a murine asthma model

Pierre Olivier Girodet, Annaig Ozier, Gabrielle Carvalho, Olga Ilina, Olga Ousova, Alain Pierre Gadeau, Hugues Begueret, Heike Wulff, Roger Marthan, Peter Bradding, Patrick Berger

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25 Scopus citations

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 Ca3.1 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 KCa3.1 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 KCa3.1 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. OVAsensitized/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 KCa3.1 blockade could provide a new therapeutic strategy in asthma.

Original languageEnglish (US)
Pages (from-to)212-219
Number of pages8
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume48
Issue number2
DOIs
StatePublished - Feb 2013

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Keywords

  • Asthma
  • Ion channel
  • K3.1
  • Remodeling
  • Smooth muscle

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Girodet, P. O., Ozier, A., Carvalho, G., Ilina, O., Ousova, O., Gadeau, A. P., Begueret, H., Wulff, H., Marthan, R., Bradding, P., & Berger, P. (2013). Ca2+-activated K+ channel-3.1 blocker TRAM-34 attenuates airway remodeling and eosinophilia in a murine asthma model. American Journal of Respiratory Cell and Molecular Biology, 48(2), 212-219. https://doi.org/10.1165/rcmb.2012-0103OC