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Mitogen-activated protein kinases regulate susceptibility to ventilator-induced lung injury

Dolinay, T and Wu, W and Kaminski, N and Ifedigbo, E and Kaynar, AM and Szilasi, M and Watkins, SC and Ryter, SW and Hoetzel, A and Choi, AMK (2008) Mitogen-activated protein kinases regulate susceptibility to ventilator-induced lung injury. PLoS ONE, 3 (2).

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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 GAFF45α. Functional characterization of MMP8 revealed that mmp8-/- mice were sensitized to ventilator-induced lung injury with increased lung vascular permeability. Conclusion: 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. © 2008 Dolinay et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Dolinay, T
Wu, W
Kaminski, N
Ifedigbo, E
Kaynar, AMkaynar@pitt.eduAMK960000-0001-8847-0450
Szilasi, M
Watkins, SC
Ryter, SW
Hoetzel, A
Choi, AMK
ContributionContributors NameEmailPitt UsernameORCID
Date: 13 February 2008
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 3
Number: 2
DOI or Unique Handle: 10.1371/journal.pone.0001601
Schools and Programs: School of Medicine > Critical Care Medicine
Refereed: Yes
PubMed ID: 18270588
Date Deposited: 18 Jul 2012 20:54
Last Modified: 22 Jun 2021 10:55


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