期刊
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
卷 287, 期 2, 页码 L279-L285出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00348.2003
关键词
ozone; nuclear factor-kappa B; interleukin-10; CCAAT/enhancer-binding protein
资金
- NCI NIH HHS [CA-100994] Funding Source: Medline
- NIEHS NIH HHS [ES-04738, ES-06897, ES-05022] Funding Source: Medline
- NIGMS NIH HHS [GM-34310] Funding Source: Medline
Ozone-induced lung injury is associated with increased production of reactive nitrogen intermediates and TNF-alpha, which have been implicated in the pathogenic process. Generation of these mediators is regulated in part by transcription factors, e. g., NF-kappaB and CCAAT/enhancer-binding protein (C/EBP). The present studies used NF-kappaB 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-kappaB binding activity in alveolar macrophages that peaked after 6 - 12 h. This response was attenuated in NF-kappaB p50(-/-) mice. In WT mice, but not NF-kappaB 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-alpha following ozone inhalation, this was not observed in cells from NF-kappaB p50(-/-) mice. Ozone-induced decreases in expression of the anti-inflammatory cytokine IL-10 were also prevented in NF-kappaB 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-kappaB p50(-/-) mice. There was also no evidence of peroxynitrite-mediated lung injury in these mice. These findings demonstrate that NF-kappaB and possibly C/EBP signaling are important in ozone-induced production of reactive nitrogen intermediates and TNF-alpha and in tissue injury.
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