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FASEB J. 2013 Dec;27(12):4975-86. doi: 10.1096/fj.13-235176. Epub 2013 Aug 30.

Treatment of experimental asthma using a single small molecule with anti-inflammatory and BK channel-activating properties.

Author information

1
1S.O.M., Columbia University, 630 West 168th St., P&S 9-420, New York, NY 10032, USA. sm460@columbia.edu; A.R.M., Columbia University, Russ Berrie Medical Science Pavilion, 1150 St. Nicholas Avenue, Room 520, New York, NY 10032, USA. E-mail: arm42@columbia.edu.

Abstract

Large conductance voltage- and calcium-activated potassium (BK) channels are highly expressed in airway smooth muscle (ASM). Utilizing the ovalbumin (OVA) and house dust mite (HDM) models of asthma in C57BL/6 mice, we demonstrate that systemic administration of the BK channel agonist rottlerin (5 μg/g) during the challenge period reduced methacholine-induced airway hyperreactivity (AHR) in OVA- and HDM-sensitized mice (47% decrease in peak airway resistance in OVA-asthma animals, P<0.01; 54% decrease in HDM-asthma animals, P<0.01) with a 35-40% reduction in inflammatory cells and 20-35% reduction in Th2 cytokines in bronchoalveolar lavage fluid. Intravenous rottlerin (5 μg/g) reduced AHR within 5 min in the OVA-asthma mice by 45% (P<0.01). With the use of an ex vivo lung slice technique, rottlerin relaxed acetylcholine-stimulated murine airway lumen area to 87 ± 4% of the precontracted area (P<0.01 vs. DMSO control). Rottlerin increased BK channel activity in human ASM cells (V50 shifted by 73.5±13.5 and 71.8±14.6 mV in control and asthmatic cells, respectively, both P<0.05 as compared with pretreatment) and reduced the frequency of acetylcholine-induced Ca(2+) oscillations in murine ex vivo lung slices. These findings suggest that rottlerin, with both anti-inflammatory and ASM relaxation properties, may have benefit in treating asthma.

KEYWORDS:

ERK; MAP kinases; airway contractility; airway smooth muscle

PMID:
23995289
PMCID:
PMC3834782
DOI:
10.1096/fj.13-235176
[Indexed for MEDLINE]
Free PMC Article

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