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dc.contributor.authorDolinay, Tamás
dc.contributor.authorWu, Wei
dc.contributor.authorKaminski, Naftali
dc.contributor.authorIfedigbo, Emeka
dc.contributor.authorKaynar, A. Murat
dc.contributor.authorSzilasi, Mária
dc.contributor.authorWatkins, Simon C.
dc.contributor.authorRyter, Stefan W.
dc.contributor.authorHoetzel, Alexander
dc.contributor.authorChoi, Augustine M.K.
dc.date.accessioned2011-04-23T17:00:54Z
dc.date.issued2008
dc.identifier.citationDolinay, Tamás, Wei Wu, Naftali Kaminski, Emeka Ifedigbo, A. Murat Kaynar, Mária Szilasi, Simon C. Watkins, Stefan W. Ryter, Alexander Hoetzel, and Augustine M. K. Choi. 2008. Mitogen-activated protein kinases regulate susceptibility to ventilator-induced lung injury. PLoS ONE 3(2): e1601.en_US
dc.identifier.issn1932-6203en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:4874804
dc.description.abstractBackground: Mechanical ventilation causes ventilator-induced lung injury in animals and humans. Mitogen-activated protein kinases have been implicated in ventilator-induced lung injury though their functional significance remains incomplete. We characterize the role of p38 mitogen-activated protein kinase/mitogen activated protein kinase kinase-3 and c-Jun-NH2-terminal kinase-1 in ventilator-induced lung injury and investigate novel independent mechanisms contributing to lung injury during mechanical ventilation. Methodology and Principle Findings: C57/BL6 wild-type mice and mice genetically deleted for mitogen-activated protein kinase kinase-3 (mkk-3−/−) or c-Jun-NH2-terminal kinase-1 (jnk1−/−) were ventilated, and lung injury parameters were assessed. We demonstrate that mkk3−/− or jnk1−/− mice displayed significantly reduced inflammatory lung injury and apoptosis relative to wild-type mice. Since jnk1−/− mice were highly resistant to ventilator-induced lung injury, we performed comprehensive gene expression profiling of ventilated wild-type or jnk1−/− mice to identify novel candidate genes which may play critical roles in the pathogenesis of ventilator-induced lung injury. Microarray analysis revealed many novel genes differentially expressed by ventilation including matrix metalloproteinase-8 (MMP8) and GADD45α. Functional characterization of MMP8 revealed that mmp8−/− mice were sensitized to ventilator-induced lung injury with increased lung vascular permeability. Conclusions: We demonstrate that mitogen-activated protein kinase pathways mediate inflammatory lung injury during ventilator-induced lung injury. C-Jun-NH2-terminal kinase was also involved in alveolo-capillary leakage and edema formation, whereas MMP8 inhibited alveolo-capillary protein leakage.en_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi:10.1371/journal.pone.0001601en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2223071/pdf/en_US
dash.licenseLAA
dc.subjectrespiratory medicineen_US
dc.subjectcell biologyen_US
dc.subjectcell signalingen_US
dc.subjectcellular death and stress responsesen_US
dc.subjectcomputational biologyen_US
dc.subjectgenomicsen_US
dc.subjectrespiratory failureen_US
dc.titleMitogen-Activated Protein Kinases Regulate Susceptibility to Ventilator-Induced Lung Injuryen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS ONEen_US
dash.depositing.authorChoi, Augustine M.K.
dc.date.available2011-04-23T17:00:54Z
dash.affiliation.otherHMS^Medicine-Brigham and Women's Hospitalen_US
dash.affiliation.otherSPH^Molecular+Integrative Physiological Sci Progen_US
dc.identifier.doi10.1371/journal.pone.0001601*
dash.contributor.affiliatedChoi, Augustine M.K.
dash.contributor.affiliatedRyter, Stefan W.


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