Peritonitis-induced peroxynitrite and lung damage depends on c-Jun NH2-terminal kinase signaling of hematopoietic cells.
OBJECTIVE
Abdominal sepsis is a common, life-threatening condition in critically ill patients, and pseudomonas peritonitis remains a serious clinical complication of peritoneal dialysis. This study was performed to determine whether peritonitis induces lung damage through the c-Jun NH2-terminal kinase.


METHODS
: Prospective, experimental study.


METHODS
Research laboratory at a university hospital.


METHODS
Peritonitis models in the mice.


METHODS
Wild-type, c-Jun NH2-terminal kinase1, and c-Jun NH2-terminal kinase1 mice were subjected to peritonitis. A c-Jun NH2-terminal kinase inhibitor, SP600125 or leflunomide, was administered to mice immediately after peritonitis.


RESULTS
The changes of plasma dihydrorhodamine 123 oxidation level, the myeloperoxidase activity, and extravasations of Evans blue dye of lung in wild-type mice with or without c-Jun NH2-terminal kinase inhibitor; c-Jun NH2-terminal kinase1 mice and c-Jun NH2-terminal kinase1 mice; and chimeric mice (wild-type --> wild-type, c-Jun NH2-terminal kinase1 --> wild-type) with Pseudomonas aeruginosa-induced peritonitis were determined to evaluate the role of c-Jun NH2-terminal kinase signaling of the hematopoietic cells in peritonitis-induced lung damage. Our results showed that peritonitis induced dihydrorhodamine 123 oxidation, myeloperoxidase activity, activator protein-1 (AP-1) DNA binding activity, phosphorylated-c-Jun NH2-terminal kinase and inducible nitric oxide synthase expression, and Evans blue dye extravasations in lungs, and administration of specific c-Jun NH2-terminal kinase inhibitor decreased the peritonitis-induced dihydrorhodamine 123 oxidation and lung damage. Also, both c-Jun NH2-terminal kinase1 and c-Jun NH2-terminal kinase1 mice showed a decreased dihydrorhodamine 123 oxidation and lung damage after peritonitis. Finally, dihydrorhodamine 123 oxidation, reactive oxygen species, inducible nitric oxide synthase expression, and lung damage were decreased in c-Jun NH2-terminal kinase1 --> wild-type but not in wild-type --> c-Jun NH2-terminal kinase1 chimeric mice.


CONCLUSIONS
Collectively, our data suggest that peritonitis-induced inducible nitric oxide synthase expression, peroxynitrite production, and lung damage depend on the c-Jun NH2-terminal kinase signaling of the hematopoietic cells.
Institute of Emergency and Critical Care Medicine, National Yang-Ming University, Taipei, Taiwan. chenlw2001@yahoo.com.tw
Lee-Wei
LW
Chen
Hsiu-Ting
HT
Tseng
Pei-Hsuan
PH
Chen
Ching-Mei
CM
Hsu
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D015153:Blotting, Western; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004195:Disease Models, Animal; D006410:Hematopoiesis / Q000502:physiology*; D007555:Isoxazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D000077339:Leflunomide; D055370:Lung Injury / Q000209:etiology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D010538:Peritonitis / Q000150:complications* / Q000503:physiopathology; D030421:Peroxynitrous Acid / Q000096:biosynthesis* / Q000502:physiology; D012235:Rhodamines / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism
D000873:Anthracenes; D007555:Isoxazoles; D016328:NF-kappa B; D012235:Rhodamines; D018808:Transcription Factor AP-1; C058319:dihydrorhodamine 123; D030421:Peroxynitrous Acid; C432165:pyrazolanthrone; D019001:Nitric Oxide Synthase; D048031:JNK Mitogen-Activated Protein Kinases; D000077339:Leflunomide; D004121:Dimethyl Sulfoxide