Hyperoxia increases ventilator-induced lung injury via mitogen-activated protein kinases: a prospective, controlled animal experiment.
BACKGROUND
Large-tidal volume (VT) mechanical ventilation and hyperoxia used in patients with acute respiratory distress syndrome can damage pulmonary epithelial cells through lung inflammation and apoptotic cell death. Hyperoxia has been shown to increase ventilator-induced lung injury, but the mechanisms regulating interaction between large VT and hyperoxia are unclear. We hypothesized that the addition of hyperoxia to large-VT ventilation would increase neutrophil infiltration by upregulation of the cytokine macrophage inflammatory protein-2 (MIP-2) and would increase apoptosis via the mitogen-activated protein kinase pathways.


METHODS
C57BL/6 mice were exposed to high-VT (30 ml/kg) mechanical ventilation with room air or hyperoxia for one to five hours.


RESULTS
The addition of hyperoxia to high-VT ventilation augmented lung injury, as demonstrated by increased apoptotic cell death, neutrophil migration into the lung, MIP-2 production, MIP-2 mRNA expression, increased DNA binding activity of activator protein-1, increased microvascular permeability, and c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) 1/2 activation. Hyperoxia-induced augmentation of high-VT-induced lung injury was attenuated in JNK-deficient mice and in mice with pharmacologic inhibition of ERK activity by PD98059. However, only JNK-deficient mice, and not mice with ERK activity inhibition by PD98059, were protected from high-VT-induced lung injury without hyperoxia.


CONCLUSIONS
We conclude that hyperoxia increased high-VT-induced cytokine production, neutrophil influx, and apoptotic cell death through activation of the JNK and ERK1/2 pathways.
Li
Li-Fu
LF
Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, and Chang Gung University, Kweishan, Taoyuan 333, Taiwan. lfp3434@adm.cgmh.org.tw
Liao
Shuen-Kuei
SK
Ko
Yu-Shien
YS
Lee
Cheng-Huei
CH
Quinn
Deborah A
DA
D000818:Animals; D017209:Apoptosis; D054426:Chemokine CXCL2; D016207:Cytokines / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D018496:Hyperoxia / Q000150:complications* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008171:Lung Diseases / Q000209:etiology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015846:Monokines / Q000096:biosynthesis* / Q000235:genetics; D020556:Neutrophil Infiltration; D012333:RNA, Messenger / Q000096:biosynthesis; D012121:Respiration, Artificial / Q000009:adverse effects*
D054426:Chemokine CXCL2; D016207:Cytokines; D005419:Flavonoids; D015846:Monokines; D012333:RNA, Messenger; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one