Role of inflammatory cytokines and nitric oxide in hepatic and pulmonary toxicity

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Exposure of humans and experimental animals to inhaled irritants such as ozone, induces an acute inflammatory response and lung injury. We hypothesize that macrophage-derived inflammatory cytokines and cytotoxic mediators contribute to the pathogenic process. Treatment of rats with ozone (2 ppm, 3 h) results in damage to the alveolar epithelium and increased protein in lung lavage fluid. This is associated with an increase in the number of macrophages in the lung. We found that these cells are activated to release the proinflammatory cytokine tumor necrosis factor-α (TNFα) which has been implicated in tissue injury. Following ozone inhalation, alveolar macrophages also produce increased amounts of the cytotoxic mediator, nitric oxide. This response is time-dependent and correlated with expression of inducible nitric oxide synthase (NOS II) protein and mRNA. Inhibition of macrophages with gadolinium chloride abrogates ozone-induced inflammation, mediator production and tissue injury. These data demonstrate, that macrophages and mediators they release contribute to irritant-induced lung injury. Ozone inhalation also caused alterations in the liver, including increased nitric oxide production and protein synthesis suggesting that ozone induces an acute phase response. We speculate that this is mediated by cytokines such as TNFα produced by alveolar macrophages. In this regard we noted increased expression of TNFα in both lung and liver tissue. Thus cytokines produced locally by macrophages following toxicant exposure may exert pathophysiologic effects outside the target organ. Copyright (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.

Original languageEnglish (US)
Pages (from-to)289-293
Number of pages5
JournalToxicology Letters
StatePublished - Dec 28 1998

All Science Journal Classification (ASJC) codes

  • Toxicology


  • Macrophages
  • Nitric oxide
  • Ozone
  • Tumor necrosis factor


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