Ventilation-induced activation of the mitogen-activated protein kinase pathway.
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)-kappaB and nuclear translocation of the transcription factor NF-kappaB. 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. The present authors conclude that mechanical ventilation triggers specific signalling pathways, such as the mitogen-activated protein kinase and the nuclear factor-kappaB pathways, which may contribute to pulmonary inflammation and proliferation.
Uhlig
U
U
Division of Pulmonary Pharmacology, Research Center Borstel, Germany.
Haitsma
J J
JJ
Goldmann
T
T
Poelma
D L
DL
Lachmann
B
B
Uhlig
S
S
D000704:Analysis of Variance; D000818:Animals; D001784:Blood Gas Analysis; D015153:Blotting, Western; D003404:Creatinine / Q000097:blood; D046508:Culture Techniques; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases; D008168:Lung / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D011233:Precipitin Tests; D011336:Probability; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D012121:Respiration, Artificial; D012680:Sensitivity and Specificity
D003404:Creatinine; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases