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and Tissue Injury are Dependent on NF-
B p50
1 Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ, USA
2 Department of Environmental and Occupational Medicine, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ, USA; Robert Wood Johnson Medical School, Environmental and Occupational Health Sciences Institute, Piscataway, NJ, USA
3 Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ, USA; Robert Wood Johnson Medical School, Environmental and Occupational Health Sciences Institute, Piscataway, NJ, USA
* To whom correspondence should be addressed. E-mail: laskin{at}eohsi.rutgers.edu.
Ozone-induced lung injury is associated with increased production of reactive nitrogen intermediates and TNF-
which have been implicated in the pathogenic process. The generation of these mediators is regulated in part by transcription factors such as NF-
B and C/EBP. The present studies used NF-B p50 knockout mice to assess the role of this transcription factor
protein in ozone-induced inflammatory mediator production and toxicity. Treatment of wild type (WT) mice with ozone (0.8 ppm, 3 h) resulted in a rapid increase in NF-B binding activity in alveolar macrophages which peaked after 6-12 h. This response was attenuated in NF-B
p50-/- mice. In WT mice, but not NF-B p50-/- mice, C/EBP was also markedly increased in macrophages following ozone inhalation. Ozone also induced changes in the mobility of C/EBP in gel shift assays suggesting changes in the transcription factor complex which may be important in controlling inflammatory gene expression. Whereas macrophages from WT mice produced increased quantities of nitric oxide and TNF- following ozone inhalation, this was not observed in cells from NF-B p50-/- mice. Ozone-induced decreases in expression of the antiinflammatory cytokine, interleukin-10 were also prevented in NF-B p50-/- mice. In WT mice,
ozone inhalation caused an increase in bronchoalveolar lavage protein, a marker of tissue damage. This was not evident in NF-B p50-/- mice. There was also no evidence of peroxynitrite mediated lung injury in these mice. These findings demonstrate that NF-B and
possibly C/EBP signaling are important in ozone-induced production of reactive nitrogen intermediates and TNF- and in tissue injury.
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