Chen Lee-Wei, Chang Wei-Jung, Wang Jyh-Seng, Hsu Ching-Mei
Department of Surgery, Kaohsiung Veterans General Hospital, National Yang-Ming Medical University, Taipei, Taiwan.
Crit Care Med. 2007 Apr;35(4):1113-22. doi: 10.1097/01.CCM.0000259175.78174.B2.
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.
Prospective, experimental study.
Research laboratory at a university hospital.
Thermal injury models in the mice.
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).
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.
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.
热损伤后肺损伤的分子机制尚不清楚。本研究旨在确定白细胞介素（IL）-1是否通过c-Jun氨基末端激酶（JNK）信号通路介导烧伤诱导的诱导型一氧化氮合酶（iNOS）表达、过氧亚硝酸盐生成及肺损伤。
前瞻性实验研究。
大学医院的研究实验室。
小鼠热损伤模型。
将1型IL-1受体（IL-1R1）小鼠、肿瘤坏死因子受体超家族成员1a（Tnfrsf1a）小鼠及野生型（WT）小鼠进行30%体表面积的三度烧伤。给小鼠注射JNK抑制剂SP600125，以研究JNK通路在热损伤诱导的肺损伤中的作用。构建WT→WT、WT→IL-1R1及IL-1R1→WT嵌合小鼠，以确定造血细胞在IL-1介导的肺损伤中的作用。采集中性粒细胞并在体外用N-甲酰甲硫氨酰亮氨酰苯丙氨酸（fMLP）处理。
与Tnfrsf1a小鼠相比，IL-1R1小鼠热损伤诱导的肺损伤较轻。热损伤后，IL-1R1小鼠肺组织JNK活性较低；细胞间黏附分子（ICAM）、血管细胞黏附分子（VCAM）、趋化因子受体2（CXCR2）及巨噬细胞炎性蛋白-2（MIP2）的信使核糖核酸表达较低；髓过氧化物酶活性较低；中性粒细胞p38丝裂原活化蛋白激酶（MAPK）磷酸化水平较低。SP600125可显著降低WT小鼠热损伤诱导的血液二氢罗丹明（DHR）123氧化、iNOS表达及肺通透性，但对IL-1R1小鼠无此作用。与WT→IL-1R1嵌合小鼠相比，IL-1R1→WT嵌合小鼠热损伤诱导的肺损伤较轻。fMLP可增加WT小鼠中性粒细胞的活性氧（ROS）生成，但对IL-1R1小鼠无此作用。SP600125可降低WT小鼠中性粒细胞的ROS生成，但对IL-1R1小鼠无此作用。
热损伤诱导的肺JNK活化、肺ICAM、VCAM、CXCR2及MIP2表达以及DHR 123氧化均依赖于IL-1。抑制JNK可减轻IL-1介导的热损伤诱导的肺损伤。鉴于IL-1受体在热损伤诱导的中性粒细胞p38 MAPK磷酸化及ROS生成中起关键作用，我们得出结论：IL-1通过JNK信号通路介导热损伤诱导的iNOS表达及肺损伤。
