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CaMKII is essential for the proasthmatic effects of oxidation.

AUTHORS

Sanders PNPhilip N , Koval OM Olha M , Jaffer OA Omar A , Prasad AM Anand M , Businga TR Thomas R , Scott JA Jason A , Hayden PJ Patrick J , Luczak ED Elizabeth D , Dickey DD David D , Allamargot C Chantal , Olivier AK Alicia K , Meyerholz DK David K , Robison AJ Alfred J , Winder DG Danny G , Blackwell TS Timothy S , Dworski R Ryszard , Sammut D David , Wagner BA Brett A , Buettner GR Garry R , Pope RM Robert M , Miller FJ Francis J , Dibbern ME Megan E , Haitchi HM Hans Michael , Mohler PJ Peter J , Howarth PH Peter H , Zabner J Joseph , Kline JN Joel N , Grumbach IM Isabella M , Anderson ME Mark E . Science translational medicine. 2013 7 24; 5(195). 195ra97

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.