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

作者：Park Moo Suk; He Qianbin; Edwards Michael G; Sergew Amen; Riches David W H; Albert Richard K; Douglas Ivor S^*

来源：American Journal of Respiratory and Critical Care Medicine, 2012, 186(1): 72-81.

DOI：10.1164/rccm.201109-1593OC

• regionally injurious ventilation
• prone position
• rodent lung injury
• MKP-1/DUSP-1
• triptolide

Rationale: Mechanical ventilation induces heterogeneous lung injury by mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B. 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 H2O; 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 H2O). 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 I kappa B alpha 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 I kappa B alpha.
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-kappa B-dependent manner. MKP-1 is a potential target for modulating regional effects of injurious ventilation.

• 出版日期2012-7-1