Mitogen-activated protein kinases regulate susceptibility to ventilator-induced lung injury. Academic Article uri icon

Overview

MeSH

  • Animals
  • Capillary Permeability
  • Edema
  • Inflammation
  • Mice
  • Ventilators, Mechanical

MeSH Major

  • JNK Mitogen-Activated Protein Kinases
  • Lung Injury
  • Mitogen-Activated Protein Kinase 8
  • Respiration, Artificial

abstract

  • 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. 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 GADD45alpha. Functional characterization of MMP8 revealed that mmp8(-/-) mice were sensitized to ventilator-induced lung injury with increased lung vascular permeability. 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.

publication date

  • 2008

has subject area

  • Animals
  • Capillary Permeability
  • Edema
  • Inflammation
  • JNK Mitogen-Activated Protein Kinases
  • Lung Injury
  • Mice
  • Mitogen-Activated Protein Kinase 8
  • Respiration, Artificial
  • Ventilators, Mechanical

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2223071

Digital Object Identifier (DOI)

  • 10.1371/journal.pone.0001601

PubMed ID

  • 18270588

Additional Document Info

start page

  • e1601

volume

  • 3

number

  • 2