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1 Division of Pulmonary Pharmacology and 3 Division of Experimental and Clinical Pathology, Research Center Borstel, Borstel, Germany. 2 Dept of Anesthesiology, Erasmus Medical Center, Rotterdam, the Netherlands
CORRESPONDENCE: S. Uhlig, Division of Pulmonary Pharmacology, Research Center Borstel, Parkallee 22, D-23845, Borstel, Germany. Fax: 49 4537188778. E-mail: suhlig@fz-borstel.de
Keywords: mechanotransduction, nuclear factor-
B, overventilation, stress-activated protein kinase, ventilation-induced lung injury
Received: September 11, 2001
Accepted May 1, 2002
This study was financially supported by the Deutsche Forschungsgemeinschaft Grant DFG Uh 88/2-4 and by the International Foundation for Clinically Oriented Research (IFCOR).
Mechanical ventilation of patients can be a life-saving treatment, but also imposes additional stress on the lung. Mitogen-activated protein kinases (MAPK) represent a family of protein kinases that become phosphorylated and activated by many different forms of stress.
Using Western blot analysis, the present study analysed the effects of high distending pressure ventilation on the activation of the MAPK extracellular signal-related kinases (ERK)-1/2, c-Jun amino-terminal kinases (JNK) and p38 kinase, and on the MAPK-activated transcription factors c-Jun, ETS-like protein (Elk)-1 and activating transcription factor (ATF)-2.
In adult rats, ventilation with high pressure (45/10 peak inspiratory pressure/positive end-expiratory pressure in cmH2O) for 30 or 60 min did not affect arterial oxygenation, but resulted in enhanced phosphorylation of ERK-1/2, JNK, c-Jun, Elk-1 and ATF-2 compared to normally ventilated (13/3) rats. The activation of ERK-1/2 and JNK was located to cells resembling alveolar type II cells. In addition, high pressure ventilation enhanced phosphorylation of the inhibitor of nuclear factor (NF)-
The present authors conclude that mechanical ventilation triggers specific signalling pathways, such as the mitogen-activated protein kinase and the nuclear factor-
B and nuclear translocation of the transcription factor NF-
B. In isolated perfused mouse lungs, the MAPK/ERK kinase inhibitor U0126 prevented ventilation-induced activation of ERK-1/2 and Elk-1, but had no effect on ventilation-induced cytokine release.
B pathways, which may contribute to pulmonary inflammation and proliferation.
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