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Treatment of experimental asthma using a single small molecule with anti‐inflammatory and BK channel‐activating properties
Author(s) -
Goldklang Monica P.,
PerezZoghbi Jose F.,
Trischler Jordis,
Nkyimbeng Takwi,
Zakharov Sergey I.,
Shiomi Takayuki,
Zelonina Tina,
Marks Andrew R.,
D'Armiento Jeanine M.,
Marx Steven O.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-235176
Subject(s) - rottlerin , bronchoalveolar lavage , ovalbumin , acetylcholine , methacholine , chemistry , pharmacology , in vivo , terbutaline , ex vivo , endocrinology , potassium channel , immunology , medicine , lung , asthma , biology , in vitro , signal transduction , biochemistry , immune system , respiratory disease , protein kinase c , microbiology and biotechnology
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 ( V 50 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.—Goldklang, M. P., Perez‐Zoghbi, J. F., Trischler, J., Nkyimbeng, T., Zakharov, S. I., Shiomi, T., Zelonina, T., Marks, A. R., D'Armiento, J. M., Marx, S. O., Treatment of experimental asthma using a single small molecule with anti‐inflammatory and BK channel‐activating properties. FASEB J. 27, 4975–4986 (2013). www.fasebj.org