Journal article
Mitochondrial CaMKII inhibition in airway epithelium protects against allergic asthma
JCI insight, Vol.2(3), pp.e88297-e88297
02/09/2017
DOI: 10.1172/jci.insight.88297
PMCID: PMC5291733
PMID: 28194433
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 Ca
/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
. Mitochondrial CaMKII inhibition abrogated AHR, inflammation, and eosinophilia following OVA and
.
challenge. 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.
Details
- Title: Subtitle
- Mitochondrial CaMKII inhibition in airway epithelium protects against allergic asthma
- Creators
- Sara C Sebag - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USAOlha M Koval - Veterans Affairs Healthcare System, Iowa City, Iowa, USAJohn D Paschke - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USAChristopher J Winters - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USAOmar A Jaffer - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USARyszard Dworski - Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, Tennessee, USAFayyaz S Sutterwala - Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USAMark E Anderson - Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USAIsabella M Grumbach - Veterans Affairs Healthcare System, Iowa City, Iowa, USA
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.2(3), pp.e88297-e88297
- DOI
- 10.1172/jci.insight.88297
- PMID
- 28194433
- PMCID
- PMC5291733
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Grant note
- K23 HL080030 / NHLBI NIH HHS R01 HL113001 / NHLBI NIH HHS R01 AI118719 / NIAID NIH HHS R01 HL108932 / NHLBI NIH HHS R01 HL070250 / NHLBI NIH HHS R56 AI118719 / NIAID NIH HHS M01 RR000095 / NCRR NIH HHS
- Language
- English
- Date published
- 02/09/2017
- Academic Unit
- Anatomy and Cell Biology; Cardiovascular Medicine; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984094532002771
Metrics
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