title: CaMKII is essential for the proasthmatic effects of oxidation.
abstract: Increased reactive oxygen species (ROS) contribute to asthma, but little is known about the molecular mechanisms connecting increased ROS with characteristic features of asthma. We show that enhanced oxidative activation of the Ca(2+)/calmodulin-dependent protein kinase (ox-CaMKII) in bronchial epithelium positively correlates with asthma severity and that epithelial ox-CaMKII increases in response to inhaled allergens in patients. We used mouse models of allergic airway disease induced by ovalbumin (OVA) or Aspergillus fumigatus (Asp) and found that bronchial epithelial ox-CaMKII was required to increase a ROS- and picrotoxin-sensitive Cl(-) current (ICl) and MUC5AC expression, upstream events in asthma progression. Allergen challenge increased epithelial ROS by activating NADPH oxidases. Mice lacking functional NADPH oxidases due to knockout of p47 and mice with epithelial-targeted transgenic expression of a CaMKII inhibitory peptide or wild-type mice treated with inhaled KN-93, an experimental small-molecule CaMKII antagonist, were protected against increases in ICl, MUC5AC expression, and airway hyperreactivity to inhaled methacholine. Our findings support the view that CaMKII is a ROS-responsive, pluripotent proasthmatic signal and provide proof-of-concept evidence that CaMKII is a therapeutic target in asthma.
authors.affiliation: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Philip N
authors.initials: PN
authors.lastname: Sanders
authors.forename: Olha M
authors.initials: OM
authors.lastname: Koval
authors.forename: Omar A
authors.initials: OA
authors.lastname: Jaffer
authors.forename: Anand M
authors.initials: AM
authors.lastname: Prasad
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Businga
authors.forename: Jason A
authors.initials: JA
authors.lastname: Scott
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Hayden
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Luczak
authors.forename: David D
authors.initials: DD
authors.lastname: Dickey
authors.forename: Chantal
authors.initials: C
authors.lastname: Allamargot
authors.forename: Alicia K
authors.initials: AK
authors.lastname: Olivier
authors.forename: David K
authors.initials: DK
authors.lastname: Meyerholz
authors.forename: Alfred J
authors.initials: AJ
authors.lastname: Robison
authors.forename: Danny G
authors.initials: DG
authors.lastname: Winder
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.forename: Ryszard
authors.initials: R
authors.lastname: Dworski
authors.forename: David
authors.initials: D
authors.lastname: Sammut
authors.forename: Brett A
authors.initials: BA
authors.lastname: Wagner
authors.forename: Garry R
authors.initials: GR
authors.lastname: Buettner
authors.forename: Robert M
authors.initials: RM
authors.lastname: Pope
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Miller
authors.forename: Megan E
authors.initials: ME
authors.lastname: Dibbern
authors.forename: Hans Michael
authors.initials: HM
authors.lastname: Haitchi
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.forename: Peter H
authors.initials: PH
authors.lastname: Howarth
authors.forename: Joseph
authors.initials: J
authors.lastname: Zabner
authors.forename: Joel N
authors.initials: JN
authors.lastname: Kline
authors.forename: Isabella M
authors.initials: IM
authors.lastname: Grumbach
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism; D001596:Benzylamines / Q000008:administration & dosage / Q000627:therapeutic use; D015153:Blotting, Western; D001980:Bronchi / Q000378:metabolism / Q000473:pathology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism; D010047:Ovalbumin / Q000494:pharmacology; D010084:Oxidation-Reduction; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use; D000096926:Benzenesulfonamides
chemical_list: D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D019255:NADPH Oxidases; D010047:Ovalbumin; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides