title: Mitochondrial CaMKII inhibition in airway epithelium protects against allergic asthma.
abstract: 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 orAspergillus fumigatus. Mitochondrial CaMKII inhibition abrogated AHR, inflammation, and eosinophilia following OVA andA.fumigatuschallenge. Mitochondrial ROS were decreased after agonist stimulation in the presence of mitochondrial CaMKII inhibition. This correlated with blunted induction of NF-κB, the NLRP3 inflammasome, and eosinophilia in transgenic mice. These findings demonstrate a pivotal role for mitochondrial CaMKII in airway epithelium in mitochondrial ROS generation, eosinophilic inflammation, and AHR, providing insights into how mitochondrial ROS mediate features of allergic asthma.
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Sara C
authors.initials: SC
authors.lastname: Sebag
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.|Veterans Affairs Healthcare System, Iowa City, Iowa, USA.
authors.forename: Olha M
authors.initials: OM
authors.lastname: Koval
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Paschke
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Winters
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Omar A
authors.initials: OA
authors.lastname: Jaffer
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Ryszard
authors.initials: R
authors.lastname: Dworski
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.|Veterans Affairs Healthcare System, Iowa City, Iowa, USA.|Inflammation Program, University of Iowa, Iowa City, Iowa, USA.|Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Fayyaz S
authors.initials: FS
authors.lastname: Sutterwala
authors.affiliation: Department of Medicine and.|Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.|Veterans Affairs Healthcare System, Iowa City, Iowa, USA.
authors.forename: Isabella M
authors.initials: IM
authors.lastname: Grumbach
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage* / Q000494:pharmacology; D001232:Aspergillus fumigatus / Q000472:pathogenicity; D001249:Asthma / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism; D010047:Ovalbumin / Q000009:adverse effects; D010455:Peptides / Q000008:administration & dosage* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D010455:Peptides; D017382:Reactive Oxygen Species; D010047:Ovalbumin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2