Inhibition of nuclear factor of activated T cells (NFAT) c3 activation attenuates acute lung injury and pulmonary edema in murine models of sepsis
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Manjula Karpurapu1, Yong Gyu Lee1, Ziqing Qian2, Jin Wen2, Megan N. Ballinger1, Luiza Rusu1, Sangwoon Chung1, Jing Deng1, Feng Qian1, Brenda F. Reader1, Teja Srinivas Nirujogi1, Gye Young Park3, Dehua Pei2 and John W. Christman1
1Pulmonary, Allergy, Critical Care and Sleep Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, OH 43210, USA
2Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA
3Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Illinois, Chicago, IL 60612, USA
John W. Christman, email: [email protected]
Manjula Karpurapu, email: [email protected]
Keywords: macrophage; NFAT’s; acute lung injury; pulmonary edema; CP9-ZIZIT
Received: September 27, 2016 Accepted: December 22, 2017 Published: January 25, 2018
Specific therapies targeting cellular and molecular events of sepsis induced Acute Lung Injury (ALI) pathogenesis are lacking. We have reported a pivotal role for Nuclear Factors of Activated T cells (NFATc3) in regulating macrophage phenotype during sepsis induced ALI and subsequent studies demonstrate that NFATc3 transcriptionally regulates macrophage CCR2 and TNFα gene expression. Mouse pulmonary microvascular endothelial cell monolayer maintained a tighter barrier function when co-cultured with LPS stimulated NFATc3 deficient macrophages whereas wild type macrophages caused leaky monolayer barrier. More importantly, NFATc3 deficient mice showed decreased neutrophilic lung inflammation, improved alveolar capillary barrier function, arterial oxygen saturation and survival benefit in lethal CLP sepsis mouse models. In addition, survival of wild type mice subjected to the lethal CLP sepsis was not improved with broad-spectrum antibiotics, whereas the survival of NFATc3 deficient mice was improved to 40–60% when treated with imipenem. Passive adoptive transfer of NFATc3 deficient macrophages conferred protection against LPS induced ALI in wild type mice. Furthermore, CP9-ZIZIT, a highly potent, cell-permeable peptide inhibitor of Calcineurin inhibited NFATc3 activation. CP9-ZIZIT effectively reduced sepsis induced inflammatory cytokines and pulmonary edema in mice. Thus, this study demonstrates that inhibition of NFATc3 activation by CP9-ZIZIT provides a potential therapeutic option for attenuating sepsis induced ALI/pulmonary edema.
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