title: Treatment of experimental asthma using a single small molecule with anti-inflammatory and BK channel-activating properties.
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.
authors.affiliation: 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.
authors.forename: Monica P
authors.initials: MP
authors.lastname: Goldklang
authors.forename: Jose F
authors.initials: JF
authors.lastname: Perez-Zoghbi
authors.forename: Jordis
authors.initials: J
authors.lastname: Trischler
authors.forename: Takwi
authors.initials: T
authors.lastname: Nkyimbeng
authors.forename: Sergey I
authors.initials: SI
authors.lastname: Zakharov
authors.forename: Takayuki
authors.initials: T
authors.lastname: Shiomi
authors.forename: Tina
authors.initials: T
authors.lastname: Zelonina
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Marks
authors.forename: Jeanine M
authors.initials: JM
authors.lastname: D'Armiento
authors.forename: Steven O
authors.initials: SO
authors.lastname: Marx
mesh_terms: D000098:Acetophenones / Q000494:pharmacology / Q000627:therapeutic use*; D000200:Action Potentials; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D039741:Antigens, Dermatophagoides / Q000633:toxicity; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy*; D001578:Benzopyrans / Q000494:pharmacology / Q000627:therapeutic use*; D020013:Calcium Signaling; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000819:agonists* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000502:physiology; D010047:Ovalbumin / Q000633:toxicity; D014132:Trachea / Q000187:drug effects / Q000473:pathology
chemical_list: D000098:Acetophenones; D000893:Anti-Inflammatory Agents; D039741:Antigens, Dermatophagoides; D001578:Benzopyrans; D051036:Large-Conductance Calcium-Activated Potassium Channels; D010047:Ovalbumin; C085746:rottlerin
keywords: ERK; MAP kinases; airway contractility; airway smooth muscle