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Signal Transduction Pathways of Tumor Necrosis Factor–mediatedLungInjuryInducedbyOzoneinMice

By Hye-youn Cho, Daniel L. Morgan, Alison K. Bauer and Steven R. Kleeberger

Abstract

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 inTnfr�/ � 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

Topics: tumor necrosis factor receptor, knockout
Year: 2013
OAI identifier: oai:CiteSeerX.psu:10.1.1.320.5749
Provided by: CiteSeerX
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