Deficiency in the c-Jun NH2-terminal kinase signaling pathway confers susceptibility to hyperoxic lung injury in mice
Deficiency in the c-Jun NH2-terminal kinase signaling pathway confers susceptibility to hyperoxic lung injury in mice
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DOI：
10.1152/ajplung.00387.2002
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发表时间：
2003-07-01
影响因子：
4.9
通讯作者：
Choi, AMK
中科院分区：
文献类型：
--
作者：
Morse, D;Otterbein, LE;Choi, AMK
高氧在小鼠肺中产生氧化应激，激活主要的应激诱导激酶途径，包括c-Jun nh2末端激酶（JNK）。我们检测了Jnk1基因缺失对小鼠体内高氧反应的影响。暴露于持续高氧后，Jnk1（-/-）小鼠的存活率相对于野生型小鼠降低。高氧65 h后，Jnk1（-/-）小鼠在支气管肺泡灌洗（BAL）液中蛋白浓度升高，血红素加氧酶-1（应激诱导基因）表达增加。与其他损伤标志物相反，Jnk1（-/-）小鼠BAL液中的白细胞计数相对于野生型小鼠明显减少。在基线或高氧治疗后，BAL白细胞计数的降低与任何髓过氧化物酶活性的降低无关。在Jnk1（-/-）和野生型小鼠中，吸入脂多糖预处理增加BAL中性粒细胞含量和延长高氧生存时间的程度相似。与野生型小鼠相比，Jnk1（-/-）小鼠暴露于高氧后肺上皮细胞凋亡增加，与死亡率增加相关。这些结果表明JNK通路参与小鼠对高氧的适应性反应。
Hyperoxia generates an oxidative stress in the mouse lung, which activates the major stress-inducible kinase pathways, including c-Jun NH2-terminal kinase (JNK). We examined the effect of Jnk1 gene deletion on in vivo responses to hyperoxia in mice. The survival of Jnk1(-/-) mice was reduced relative to wild-type mice after exposure to continuous hyperoxia. Jnk1(-/-) mice displayed higher protein concentration in bronchoalveolar lavage (BAL) fluid and increased expression of heme oxygenase-1, a stress-inducible gene, after 65 h of hyperoxia. Contrary to other markers of injury, the leukocyte count in BAL fluid of Jnk1(-/-) mice was markedly diminished relative to that of wild-type mice. The decrease in BAL leukocyte count was not associated with any decrease in lung myeloperoxidase activity at baseline or after hyperoxia treatment. Pretreatment with inhaled lipopolysaccharide increased BAL neutrophil content and extended hyperoxia survival time to a similar extent in Jnk1(-/-) and wild-type mice. Associated with increased mortality, Jnk1(-/-) mice had increased pulmonary epithelial cell apoptosis after exposure to hyperoxia compared with wild-type mice. These results indicate that JNK pathways participate in adaptive responses to hyperoxia in mice.