Asthma: CaMKII is essential for the proasthmatic effects of oxidation

Philip N. Sanders, Olha M. Koval, Omar A. Jaffer, Anand M. Prasad, Thomas R. Businga, Jason A. Scott, Patrick J. Hayden, Elizabeth D. Luczak, David D. Dickey, Chantal Allamargot, Alicia K. Olivier, David K. Meyerholz, Alfred J. Robison, Danny G. Winder, Timothy S. Blackwell, Ryszard Dworski, David Sammut, Brett A. Wagner, Garry R. Buettner, Robert M. PopeFrancis J. Miller, Megan E. Dibbern, Hans Michael Haitchi, Peter J. Mohler, Peter H. Howarth, Joseph Zabner, Joel N. Kline, Isabella M. Grumbach, Mark E. Anderson

Research output: Contribution to journalArticle

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 Ca2+/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 smallmolecule 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.

Original languageEnglish (US)
Article number195ra97
JournalScience translational medicine
Volume5
Issue number195
DOIs
StatePublished - Jul 24 2013
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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    Sanders, P. N., Koval, O. M., Jaffer, O. A., Prasad, A. M., Businga, T. R., Scott, J. A., Hayden, P. J., Luczak, E. D., Dickey, D. D., Allamargot, C., Olivier, A. K., Meyerholz, D. K., Robison, A. J., Winder, D. G., Blackwell, T. S., Dworski, R., Sammut, D., Wagner, B. A., Buettner, G. R., ... Anderson, M. E. (2013). Asthma: CaMKII is essential for the proasthmatic effects of oxidation. Science translational medicine, 5(195), [195ra97]. https://doi.org/10.1126/scitranslmed.3006135