title: Mitogen-activated protein kinase phosphatase-1 modulates regional effects of injurious mechanical ventilation in rodent lungs.
abstract: BACKGROUND
  Mechanical ventilation induces heterogeneous lung injury by mitogen-activated protein kinase (MAPK) and nuclear factor-κB. Mechanisms regulating regional injury and protective effects of prone positioning are unclear.
  
  
  OBJECTIVE
  To determine the key regulators of the lung regional protective effects of prone positioning in rodent lungs exposed to injurious ventilation.
  
  
  METHODS
  Adult rats were ventilated with high (18 ml/kg, positive end-expiratory pressure [PEEP] 0) or low Vt (6 ml/kg; PEEP 3 cm H(2)O; 3 h) in supine or prone position. Dorsal-caudal lung mRNA was analyzed by microarray and MAPK phosphatases (MKP)-1 quantitative polymerase chain reaction. MKP-1(-/-) or wild-type mice were ventilated with very high (24 ml/kg; PEEP 0) or low Vt (6-7 ml/kg; PEEP 3 cm H(2)O). The MKP-1 regulator PG490-88 (MRx-108; 0.75 mg/kg) or phosphate-buffered saline was administered preventilation. Injury was assessed by lung mechanics, bronchioalveolar lavage cell counts, protein content, and lung injury scoring. Immunoblotting for MKP-1, and IκBα and cytokine ELISAs were performed on lung lysates.
  
  
  RESULTS
  Prone positioning was protective against injurious ventilation in rats. Expression profiling demonstrated MKP-1 20-fold higher in rats ventilated prone rather than supine and regional reduction in p38 and c-jun N-terminal kinase activation. MKP-1(-/-) mice experienced amplified injury. PG490-88 improved static lung compliance and injury scores, reduced bronchioalveolar lavage cell counts and cytokine levels, and induced MKP-1 and IκBα.
  
  
  CONCLUSIONS
  Injurious ventilation induces MAPK in an MKP-1-dependent fashion. Prone positioning is protective and induces MKP-1. PG490-88 induced MKP-1 and was protective against high Vt in a nuclear factor-κB-dependent manner. MKP-1 is a potential target for modulating regional effects of injurious ventilation.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Denver Health and University of Colorado, 777 Bannock Street, Denver, CO 80204, USA.
authors.forename: Moo Suk
authors.initials: MS
authors.lastname: Park
authors.forename: Qianbin
authors.initials: Q
authors.lastname: He
authors.forename: Michael G
authors.initials: MG
authors.lastname: Edwards
authors.forename: Amen
authors.initials: A
authors.lastname: Sergew
authors.forename: David W H
authors.initials: DW
authors.lastname: Riches
authors.forename: Richard K
authors.initials: RK
authors.lastname: Albert
authors.forename: Ivor S
authors.initials: IS
authors.lastname: Douglas
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004224:Diterpenes / Q000627:therapeutic use; D015536:Down-Regulation / Q000502:physiology; D054638:Dual Specificity Phosphatase 1 / Q000502:physiology*; D020869:Gene Expression Profiling; D020672:I-kappa B Proteins / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D016133:Polymerase Chain Reaction; D016684:Prone Position / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012121:Respiration, Artificial / Q000009:adverse effects*; D016683:Supine Position / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D055397:Ventilator-Induced Lung Injury / Q000378:metabolism* / Q000517:prevention & control*
chemical_list: D004224:Diterpenes; D020672:I-kappa B Proteins; C417603:omtriptolide; D054638:Dual Specificity Phosphatase 1