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

Article

关键词: AIRWAY SMOOTH-MUSCLE;    KINASE-C-DELTA;    HOUSE-DUST MITE;    N-TERMINAL KINASE;    PROTEIN-KINASES;    MOUSE MODEL;    INTRACELLULAR CA2+;    POTASSIUM CHANNELS;    T-CELLS;    INFLAMMATION;   

DOI  :  10.1096/fj.13-235176

来源: SCIE

【 摘 要 】

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 mu g/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 mu g/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 Ca2+ 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.

【 授权许可】

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