Signal Transduction Pathways of Tumor Necrosis Factor–mediated Lung Injury Induced by Ozone in Mice

Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, 111 TW Alexander Drive, Building 101, MD D-201, Research Triangle Park, NC 27709, USA.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 05/2007; 175(8):829-39. DOI: 10.1164/rccm.200509-1527OC
Source: PubMed


Increasing evidence suggests that tumor necrosis factor (TNF)-alpha plays a key role in pulmonary injury caused by environmental ozone (O(3)) 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 O(3) exposure.
The present study was designed to determine the molecular mechanisms of TNF receptor (TNF-R)-mediated lung injury induced by O(3).
TNF-R knockout (Tnfr(-/-)) and wild-type (Tnfr(+/+)) mice were exposed to 0.3 ppm O(3) or air (for 6, 24, or 48 h), and lung RNA and proteins were prepared. Mice deficient in p50 nuclear factor (NF)-kappaB (Nfkb1(-/-)) or c-Jun-NH(2) terminal kinase 1 (Jnk1(-/-)) and wild-type controls (Nfkb1(+/+), Jnk1(+/+)) were exposed to O(3) (48 h), and the role of NF-kappaB and mitogen-activated protein kinase (MAPK) as downstream effectors of lung injury was analyzed by bronchoalveolar lavage analyses.
O(3)-induced early activation of TNF-R adaptor complex formation was attenuated in Tnfr(-/-) mice compared with Tnfr(+/+) mice. O(3) significantly activated lung NF-kappaB in Tnfr(+/+) mice before the development of lung injury. Basal and O(3)-induced NF-kappaB 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 Tnfr(-/-) and Tnfr(+/+) mice after O(3). O(3)-induced lung injury was significantly reduced in Nfkb1(-/-) and Jnk1(-/-) mice relative to respective control animals.
Results suggest that NF-kappaB and MAPK/AP-1 signaling pathways are essential in TNF-R-mediated pulmonary toxicity induced by O(3).

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Available from: Hye-Youn Cho, Jul 03, 2014
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    • "chow; Zeigler Brothers) and water ad libitum. Mice were exposed continuously to 0.3 ppm ozone for 6, 24, 48, or 72 hr as previously described (Cho et al. 2007), and parallel exposures to filtered air were performed in a separate chamber for the same duration. Ozone was generated with a silent arc discharge ozone generator (model L-11; Pacific Ozone Technology) using ultra-highpurity air (National Welders Inc.). "
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