Mitogen-activated protein kinase phosphatase-1 modulates regional effects of injurious mechanical ventilation in rodent lungs

Am J Respir Crit Care Med. 2012 Jul 1;186(1):72-81. doi: 10.1164/rccm.201109-1593OC. Epub 2012 May 10.


Rationale: 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.

Objectives: 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.

Measurements and main 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blotting, Western
  • Diterpenes / therapeutic use
  • Down-Regulation / physiology
  • Dual Specificity Phosphatase 1 / physiology*
  • Gene Expression Profiling
  • I-kappa B Proteins / metabolism
  • Lung / metabolism
  • Male
  • Polymerase Chain Reaction
  • Prone Position / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Respiration, Artificial / adverse effects*
  • Supine Position / physiology
  • Up-Regulation / physiology
  • Ventilator-Induced Lung Injury / metabolism*
  • Ventilator-Induced Lung Injury / prevention & control*


  • Diterpenes
  • I-kappa B Proteins
  • omtriptolide
  • Dual Specificity Phosphatase 1