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

By T Dolinay, W Wu, N Kaminski, E Ifedigbo, AM Kaynar, M Szilasi, SC Watkins, SW Ryter, A Hoetzel and AMK Choi

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-NH 2 -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-NH 2 -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-NH 2 -terminal kinase was also involved in alveolo-capillary leakage and edema formation, whereas MMP8 inhibited alveolo-capillary protein leakage. © 2008 Dolinay et al

Year: 2008
DOI identifier: 10.1371/journal.pone.0001601
OAI identifier: oai:d-scholarship.pitt.edu:12933
Provided by: D-Scholarship@Pitt

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