Deficiency in the c-Jun NH2-terminal kinase signaling pathway confers susceptibility to hyperoxic lung injury in mice.
Hyperoxia generates an oxidative stress in the mouse lung, which activates the major stress-inducible kinase pathways, including c-Jun NH2-terminal kinase (JNK). We examined the effect of Jnk1 gene deletion on in vivo responses to hyperoxia in mice. The survival of Jnk1-/- mice was reduced relative to wild-type mice after exposure to continuous hyperoxia. Jnk1-/- mice displayed higher protein concentration in bronchoalveolar lavage (BAL) fluid and increased expression of heme oxygenase-1, a stress-inducible gene, after 65 h of hyperoxia. Contrary to other markers of injury, the leukocyte count in BAL fluid of Jnk1-/- mice was markedly diminished relative to that of wild-type mice. The decrease in BAL leukocyte count was not associated with any decrease in lung myeloperoxidase activity at baseline or after hyperoxia treatment. Pretreatment with inhaled lipopolysaccharide increased BAL neutrophil content and extended hyperoxia survival time to a similar extent in Jnk1-/- and wild-type mice. Associated with increased mortality, Jnk1-/- mice had increased pulmonary epithelial cell apoptosis after exposure to hyperoxia compared with wild-type mice. These results indicate that JNK pathways participate in adaptive responses to hyperoxia in mice.
Morse
Danielle
D
Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Otterbein
Leo E
LE
Watkins
Simon
S
Alber
Sean
S
Zhou
Zhihong
Z
Flavell
Richard A
RA
Davis
Roger J
RJ
Choi
Augustine M K
AM
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015415:Biomarkers; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D004790:Enzyme Induction / Q000502:physiology; D017353:Gene Deletion; D018496:Hyperoxia / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides / Q000494:pharmacology; D008171:Lung Diseases / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology / Q000201:enzymology; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000502:physiology; D010100:Oxygen / Q000633:toxicity; D009195:Peroxidase / Q000378:metabolism
D015415:Biomarkers; D008070:Lipopolysaccharides; D009195:Peroxidase; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D010100:Oxygen