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

¹ Laboratory of Respiratory Biology, ² Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina

Correspondence and requests for reprints should be addressed to Hye-Youn Cho, Ph.D., 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. E-mail: cho2{at}niehs.nih.gov

Rationale: Increasing evidence suggests that tumor necrosis factor (TNF)- plays a key role in pulmonary injury caused by environmental ozone (O₃) 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 O₃ exposure.

Objectives: The present study was designed to determine the molecular mechanisms of TNF receptor (TNF-R)–mediated lung injury induced by O₃.

Methods: TNF-R knockout (Tnfr^–/–) and wild-type (Tnfr^+/+) mice were exposed to 0.3 ppm O₃ or air (for 6, 24, or 48 h), and lung RNA and proteins were prepared. Mice deficient in p50 nuclear factor (NF)-B (Nfkb1^–/–) or c-Jun–NH₂ terminal kinase 1 (Jnk1^–/–) and wild-type controls (Nfkb1^+/+, Jnk1^+/+) were exposed to O₃ (48 h), and the role of NF-B and mitogen-activated protein kinase (MAPK) as downstream effectors of lung injury was analyzed by bronchoalveolar lavage analyses.

Results: O₃-induced early activation of TNF-R adaptor complex formation was attenuated in Tnfr^–/– mice compared with Tnfr^+/+ mice. O₃ significantly activated lung NF-B in Tnfr^+/+ mice before the development of lung injury. Basal and O₃-induced NF-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 O₃. Furthermore, inflammatory cytokines, including macrophage inflammatory protein-2, were differentially expressed in Tnfr^–/– and Tnfr^+/+ mice after O₃. O₃-induced lung injury was significantly reduced in Nfkb1^–/– and Jnk1^–/– mice relative to respective control animals.

Conclusions: Results suggest that NF-B and MAPK/AP-1 signaling pathways are essential in TNF-R–mediated pulmonary toxicity induced by O₃.

Key Words: tumor necrosis factor receptor • knockout • nuclear factor-B • mitogen-activated protein kinase • activator protein-1

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Nuclear factor-B and MAPK/AP-1 signaling pathways are essential in tumor necrosis factor receptor–mediated pulmonary toxicity induced by ozone. What This Study Adds to the Field NF-B and MAPK/AP-1 signaling pathways are essential in TNF receptor–mediated lung injury induced by ozone.

 

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