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. Design. Prospective, experimental study. Setting. Research laboratory at a university hospital. Subjects. Thermal injury models in the mice. Interventions. IL-1 receptortype 1 (lL-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 -> lL-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). Measurements and Main 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.