Excessive ROS promote allergic asthma, a condition characterized by airway inflammation, eosinophilic inflammation, and increased airway hyperreactivity (AHR). The mechanisms by which airway ROS are increased and the relationship between increased airway ROS and disease phenotypes are incompletely defined. Mitochondria are an important source of cellular ROS production, and our group discovered that Ca2+/calmodulin-dependent protein kinase II (CaMKII) is present in mitochondria and activated by oxidation. Furthermore, mitochondrial-targeted antioxidant therapy reduced the severity of allergic asthma in a mouse model. Based on these findings, we developed a mouse model of CaMKII inhibition targeted to mitochondria in airway epithelium. We challenged these mice with OVA or
Sara C. Sebag, Olha M. Koval, John D. Paschke, Christopher J. Winters, Omar A. Jaffer, Ryszard Dworski, Fayyaz S. Sutterwala, Mark E. Anderson, Isabella M. Grumbach
Schematic representation of findings.
Exposure of lung epithelial cells to an allergic stimulus induces ox-CaMKII expression in mitochondria, leading to Mt-ROS generation. This in turn activates NF-κB, which, together with inflammasome expression and activation, induces the expression of Th2 cytokines, including eotaxin, IL-4, and IL-5, leading to eosinophil recruitment and infiltration as well as increased airway hyperreactivity.