Signal transduction pathways of tumor necrosis factor--mediated lung injury induced by ozone in mice.
BACKGROUND
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.


OBJECTIVE
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 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.


RESULTS
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.


CONCLUSIONS
Results suggest that NF-kappaB and MAPK/AP-1 signaling pathways are essential in TNF-R-mediated pulmonary toxicity induced by O(3).
Cho
Hye-Youn
HY
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. cho2@niehs.nih.gov
Morgan
Daniel L
DL
Bauer
Alison K
AK
Kleeberger
Steven R
SR
D000818:Animals; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology; D010126:Ozone / Q000009:adverse effects*; D012128:Respiratory Distress Syndrome / Q000139:chemically induced*; D015398:Signal Transduction / Q000502:physiology*; D047992:TNF Receptor-Associated Factor 2 / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D010126:Ozone; D020928:Mitogen-Activated Protein Kinases