Mitogen-Activated Protein Kinases Regulate Susceptibility to Ventilator-Induced Lung Injury
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Mitogen-Activated Protein Kinases Regulate Susceptibility to Ventilator-Induced Lung Injury
| Title: | Mitogen-Activated Protein Kinases Regulate Susceptibility to Ventilator-Induced Lung Injury |
| Author: |
Dolinay, Tamás; Kaminski, Naftali; Ifedigbo, Emeka; Kaynar, A. Murat; Szilasi, Mária; Watkins, Simon C.; Hoetzel, Alexander; Wu, Wei; Ryter, Stefan W.; Choi, Augustine M.K.
Note: Order does not necessarily reflect citation order of authors. |
| Citation: | Dolinay, 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. |
| Full Text & Related Files: |
2223071.pdf (633.6Kb; PDF) 
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| Abstract: | Background: 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. |
| Published Version: | doi:10.1371/journal.pone.0001601 |
| Other Sources: | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2223071/pdf/ |
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| Citable link to this page: | http://nrs.harvard.edu/urn-3:HUL.InstRepos:4874804 |
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