Peritonitis-induced peroxynitrite and lung damage depends on c-Jun NH2-terminal kinase signaling of hematopoietic cells

Objectives: 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. Design: Prospective, experimental study. Setting: Research laboratory at a university hospital. Subjects: Peritonitis models in the mice. Interventions: 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. Measurements and Main 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. (Crit Care Med 2010; 38: 1168-1178)