Interleukin-1 mediates thermal injury-induced lung damage through C-Jun NH2-terminal kinase signaling.
OBJECTIVE
The molecular mechanisms of lung damage following thermal injury are not clear. The purpose of this study was to determine whether interleukin (IL)-1 mediates burn-induced inducible nitric oxide synthase (iNOS) expression, peroxynitrite production, and lung damage through c-Jun NH2-terminal kinase (JNK) signaling.


METHODS
Prospective, experimental study.


METHODS
Research laboratory at a university hospital.


METHODS
Thermal injury models in the mice.


METHODS
IL-1 receptor type 1 (IL-1R1) mice, Tnfrsf1a mice, and wild-type (WT) mice were subjected to 30% total body surface area third-degree burn. The JNK inhibitor, SP600125, was given to mice to study the involvement of the JNK pathway in thermal injury-induced lung damage. WT --> WT, WT --> IL-1R1, and IL-1R1 --> WT chimeric mice were generated to determine the role of hematopoietic cells in IL-1-mediated lung damage. Neutrophils were harvested and treated in vitro with N-formyl-methionyl-leucyl-phenylalanine (fMLP).


RESULTS
IL-1R1 mice rather than Tnfrsf1a mice showed less thermal injury-induced lung damage. IL-1R1 mice displayed less lung JNK activity; intercellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), chemokine receptor 2 (CXCR2), and macrophage inflammatory protein-2 (MIP2), messenger RNA expression; myeloperoxidase activity; and neutrophil p38 mitogen-activated protein kinase (MAPK) phosphorylation after thermal injury. SP600125 significantly reduced thermal injury-induced blood dihydrorhodamine (DHR) 123 oxidation, iNOS expression, and lung permeability in WT mice but not in IL-1R1 mice. IL-1R1 --> WT chimeric mice rather than WT --> IL-1R1 chimeric mice showed less thermal injury-induced lung damage. fMLP increased reactive oxygen species (ROS) production of neutrophils in WT mice but not in IL-1R1 mice. SP600125 decreased ROS production of neutrophils in WT mice but not in IL-1R1 mice.


CONCLUSIONS
Thermal injury-induced lung JNK activation; lung ICAM, VCAM, CXCR2, and MIP2 expression; and DHR 123 oxidation are IL-1 dependent. JNK inhibition decreases IL-1-mediated thermal injury-induced lung damage. Given that the IL-1 receptor is critical in thermal injury-induced p38 MAPK phosphorylation and ROS production of neutrophils, we conclude that IL-1 mediates thermal injury-induced iNOS expression and lung damage through the JNK signaling pathway.
Chen
Lee-Wei
LW
Department of Surgery, Kaohsiung Veterans General Hospital, National Yang-Ming Medical University, Taipei, Taiwan. chenlw2001@yahoo.com.tw
Chang
Wei-Jung
WJ
Wang
Jyh-Seng
JS
Hsu
Ching-Mei
CM
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002056:Burns / Q000150:complications / Q000378:metabolism*; D054426:Chemokine CXCL2; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007375:Interleukin-1 / Q000378:metabolism / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008171:Lung Diseases / Q000209:etiology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015846:Monokines / Q000096:biosynthesis; D009504:Neutrophils / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D009195:Peroxidase / Q000096:biosynthesis; D030421:Peroxynitrous Acid / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics; D023063:Receptors, Interleukin-8B / Q000096:biosynthesis; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics; D015398:Signal Transduction; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
D000873:Anthracenes; D054426:Chemokine CXCL2; D007375:Interleukin-1; D015846:Monokines; D012333:RNA, Messenger; D053573:Receptors, Interleukin-1 Type I; D023063:Receptors, Interleukin-8B; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D030421:Peroxynitrous Acid; C432165:pyrazolanthrone; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases