Abstract
Increasing evidence demonstrates that Na(+), K(+)-ATPase plays an important role in pulmonary inflammation, but the mechanism remains largely unknown. In this study, we used cardiotonic steroids as Na(+), K(+)-ATPase inhibitors to explore the possible involvement of Na(+), K(+)-ATPase in pulmonary epithelial inflammation. The results demonstrated that mice after ouabain inhalation developed cyclooxygenase-2-dependent acute lung inflammation. The in vitro experiments further confirmed that Na(+), K(+)-ATPase inhibitors significantly stimulated cyclooxygenase-2 expression in lung epithelial cells of human or murine origin, the process of which was participated by multiple cis-elements and trans-acting factors. Most importantly, we first described here that Na(+), K(+)-ATPase inhibitors could evoke a significant Hu antigen R nuclear export in lung epithelial cells, which stabilized cyclooxygenase-2 mRNA by binding with a proximal AU-rich element within its 3'-untranslated region. In conclusion, HuR-mediated mRNA stabilization opens new avenues in understanding the importance of Na(+), K(+)-ATPase, as well as its inhibitors in inflammation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus
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Animals
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Antigens, Surface / metabolism
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Antigens, Surface / physiology*
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Calcium Signaling
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Cardiac Glycosides / pharmacology
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Cyclooxygenase 2 / genetics*
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Cyclooxygenase 2 / metabolism
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ELAV Proteins
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ELAV-Like Protein 1
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Enzyme Inhibitors / pharmacology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Extracellular Signal-Regulated MAP Kinases / physiology
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Humans
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Immunoprecipitation
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Lung / metabolism
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Mice
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Ouabain / pharmacology
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Pneumonia / chemically induced
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Pneumonia / enzymology
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Pneumonia / genetics*
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RNA Stability*
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RNA, Messenger / metabolism*
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RNA-Binding Proteins / metabolism
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RNA-Binding Proteins / physiology*
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Reverse Transcriptase Polymerase Chain Reaction
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Ribonucleoproteins / metabolism
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Sodium-Potassium-Exchanging ATPase / genetics
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Sodium-Potassium-Exchanging ATPase / metabolism
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Sodium-Potassium-Exchanging ATPase / physiology*
Substances
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Antigens, Surface
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Cardiac Glycosides
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ELAV Proteins
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ELAV-Like Protein 1
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ELAVL1 protein, human
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Enzyme Inhibitors
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RNA, Messenger
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RNA-Binding Proteins
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Ribonucleoproteins
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messenger ribonucleoprotein
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Ouabain
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Cyclooxygenase 2
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Extracellular Signal-Regulated MAP Kinases
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Sodium-Potassium-Exchanging ATPase