Signal transduction pathways of tumor necrosis factor-mediated lung injury induced by ozone in mice
Signal transduction pathways of tumor necrosis factor-mediated lung injury induced by ozone in mice
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DOI：
10.1164/rccm.200509-1527oc
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发表时间：
2007-04-15
影响因子：
24.7
通讯作者：
Kleeberger, Steven R.
中科院分区：
文献类型：
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作者：
Cho, Hye-Youn;Morgan, Daniel L.;Kleeberger, Steven R.
越来越多的证据表明，肿瘤坏死因子（TNF）-α在动物模型和人类受试者中由环境臭氧（01）引起的肺损伤中起着关键作用。我们先前确定，TNF反应基因缺陷的小鼠在暴露于O-3后免受肺部炎症和上皮损伤。目的：本研究旨在确定TNF受体（TNF-R）介导的O-3肺损伤的分子机制。将TNF-R敲除（Tnfr（-/-））和野生型（Tnfr（+/+））小鼠暴露于0.3ppm O3或空气（持续6、24或48小时），并制备肺RNA和蛋白质。p50核因子（NF）-κ B缺陷小鼠（Nfkb 1（-/-））或c-Jun-NH 2末端激酶1（Jnk 1（-/-））和野生型对照（Nfkb 1（+/+），Jnk（+/+））暴露于03（48小时），通过支气管肺泡灌洗分析来分析NF-κ B和丝裂原活化蛋白激酶（MAPK）作为肺损伤的下游效应物的作用。与Tnfr（+/+）小鼠相比，O-3诱导的TNF-R接头复合物形成的早期激活在Tnfr（-/-）小鼠中减弱。03显著激活Tnfr（+/+）小鼠的肺NF-κ B B，然后发生肺损伤。在Tnfr（-/-）小鼠中，基础和O-3诱导的NF-κ B活性受到抑制。与Tnfr（+/+）小鼠相比，Tnfr（-/-）小鼠的MAPKs和激活蛋白（AP）-1在基础和O-3后较低。此外，包括巨噬细胞炎性蛋白-2在内的炎性细胞因子在Trifir（-/-）和Tnfr（+/+）中差异表达。O-3后的小鼠。O-3诱导的肺损伤显着减少Nfkb 1（-/-）和JNK 1（-/-）小鼠相对于各自的control animals.Conclusions：结果表明，NF-κ B B和MAPK/AP-1信号通路是必不可少的TNF-R介导的O-3诱导的肺毒性。
Rationale Increasing evidence suggests that tumor necrosis factor (TNF)-alpha plays a key role in pulmonary injury caused by environmental ozone (01) in animal models and human subjects. We previously determined that mice genetically deficient in TNF response are protected from lung inflammation and epithelial injury after 03 exposure.Objectives: The present study was designed to determine the molecular mechanisms of TNF receptor (TNF-R)-mediated lung injury induced by O-3.Methods: TNF-R knockout (Tnfr(-/-)) and wild-type (Tnfr(+/+)) mice were exposed to 0.3 ppm 03 or air (for 6, 24, or 48 h), and lung RNA and proteins were prepared. Mice deficient in p50 nuclear factor (NF)-kappa B (Nfkb1(-/-)) or c-Jun-NH2 terminal kinase 1 (Jnk1(-/-)) and wild-type controls (Nfkb1(+/+), Jnk(+/+)) were exposed to 03 (48 h), and the role of NF-kappa B and mitogen-activated protein kinase (MAPK) as downstream effectors of lung injury was analyzed by bronchoalveolar lavage analyses.Results: O-3-induced early activation of TNF-R adaptor complex formation was attenuated in Tnfr(-/-) mice compared with Tnfr(+/+) mice. 03 significantly activated lung NF-kappa B in Tnfr(+/+) mice before the development of lung injury. Basal and O-3-induced NF-kappa B activity was suppressed in Tnfr(-/-) mice. Compared with Tnfr(+/+) mice, MAPKs and activator protein (AP)-1 were lower in Tnfr(-/-) mice basally and after O-3. Furthermore, inflammatory cytokines, including macrophage inflammatory protein-2, were differentially expressed in Trifir(-/-) and Tnfr(+/+). mice after O-3. O-3-induced lung injury was significantly reduced in Nfkb1(-/-) and Jnk1(-/-) mice relative to respective control animals.Conclusions: Results suggest that NF-kappa B and MAPK/AP-1 signaling pathways are essential in TNF-R-mediated pulmonary toxicity induced by O-3.