Mitogen-activated Protein Kinase Phosphatase-1 Modulates Regional Effects of Injurious Mechanical Ventilation in Rodent Lungs

• Published in: American journal of respiratory and critical care medicine 2012-07, Vol.186 (1), p.72-81
• Main Authors: MOO SUK PARK, QIANBIN HE, EDWARDS, Michael G, SERGEW, Amen, RICHES, David W. H, ALBERT, Richard K, DOUGLAS, Ivor S
• Format: Article
• Language: English
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Biological and medical sciences; Blotting, Western; Cytokines; Diterpenes - therapeutic use; Down-Regulation - physiology; Dual Specificity Phosphatase 1 - physiology; Emergency and intensive respiratory care; Gene Expression Profiling; I-kappa B Proteins - metabolism; Intensive care medicine; Kinases; Lung - metabolism; Lungs; Male; Medical sciences; Patient positioning; Phosphatase; Polymerase Chain Reaction; Prone Position - physiology; Proteins; Rats; Rats, Sprague-Dawley; Respiration, Artificial - adverse effects; Respiratory distress syndrome; Rodents; Supine Position - physiology; Up-Regulation - physiology; Ventilation; Ventilator-Induced Lung Injury - metabolism; Ventilator-Induced Lung Injury - prevention & control
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.201109-1593OC

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. To determine the key regulators of the lung regional protective effects of prone positioning in rodent lungs exposed to injurious ventilation. 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. 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. 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.