title: Mitogen-activated protein kinases regulate susceptibility to ventilator-induced lung injury.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Tamás
authors.initials: T
authors.lastname: Dolinay
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
authors.forename: Emeka
authors.initials: E
authors.lastname: Ifedigbo
authors.forename: A Murat
authors.initials: AM
authors.lastname: Kaynar
authors.forename: Mária
authors.initials: M
authors.lastname: Szilasi
authors.forename: Simon C
authors.initials: SC
authors.lastname: Watkins
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoetzel
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D004487:Edema; D007249:Inflammation / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D055370:Lung Injury; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8 / Q000502:physiology*; D012121:Respiration, Artificial / Q000009:adverse effects*; D012122:Ventilators, Mechanical / Q000009:adverse effects
chemical_list: D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8