Ozone-induced production of nitric oxide and TNF-α and tissue injury are dependent on NF-κB p50

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Abstract

Ozone-induced lung injury is associated with increased production of reactive nitrogen intermediates and TNF-α, which have been implicated in the pathogenic process. Generation of these mediators is regulated in part by transcription factors, e.g., NF-κB and CCAAT/enhancer-binding protein (C/EBP). The present studies used NF-κB 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-κB binding activity in alveolar macrophages that peaked after 6-12 h. This response was attenuated in NF-κB p50-/- mice. In WT mice, but not NF-κB 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 alterations in the transcription factor complex that may be important in controlling inflammatory gene expression. Whereas macrophages from WT mice produced increased quantities of nitric oxide and TNF-α following ozone inhalation, this was not observed in cells from NF-κB p50-/- mice. Ozone-induced decreases in expression of the anti-inflammatory cytokine IL-10 were also prevented in NF-κB 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-κB p50-/- mice. There was also no evidence of peroxynitrite-mediated lung injury in these mice. These findings demonstrate that NF-κB and possibly C/EBP signaling are important in ozone-induced production of reactive nitrogen intermediates and TNF-α and in tissue injury.

Original languageEnglish (US)
Pages (from-to)L279-L285
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume287
Issue number2 31-2
DOIs
StatePublished - Aug 2004

All Science Journal Classification (ASJC) codes

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Keywords

  • CCAAT/enhancer-binding protein
  • Interleukin-10
  • Nuclear factor-κB
  • Ozone

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