Nitrogen dioxide exposure attenuates cigarette smoke-induced cytokine production in mice

Inhal Toxicol. 2008 Jan;20(2):183-9. doi: 10.1080/08958370701821342.


Cigarette smoke is the most important cause for the development of chronic obstructive pulmonary disease (COPD). Since only a minority of smokers and some nonsmokers develop COPD, other factors must be involved as well. NO2 is an important air pollutant associated with respiratory symptoms in humans and emphysema development in animal models. We hypothesized that combined exposure to NO2 and cigarette smoke will enhance pulmonary inflammation and emphysema development. Mice were exposed to 20 ppm NO2 for 17 h/day, to 24 puffs of cigarette smoke 2 times per day, to their combination, or to control air for 5 days/wk during 4 wk. Following the last NO2 exposure and within 24 h after the last smoke exposure the mice were sacrificed. Lungs were removed and analyzed for several inflammatory parameters and emphysema. Cigarette smoke exposure increased eosinophil numbers and levels of tumor necrosis factor (TNF)-alpha, KC, monocyte chemoattractant protein (MCP)-1, and interleukin (IL)-6. NO2 exposure increased goblet cells, eosinophils, and the levels of IL-6, while it decreased the levels of IL-10. Four weeks of NO2, cigarette smoke, or their combination was not sufficient to induce significant emphysema, nor did it lead to increased numbers of lymphocytes, neutrophils, or macrophages in lung tissue. Instead, NO2 exposure attenuated the smoke-induced increases in levels of TNF-alpha, KC, and MCP-1. These dampening effects of NO2 may be due to modulating effects of NO2 on cytokine production by macrophages and epithelial cells, which have been reported earlier. The next step is to translate these findings of combined, controlled exposure in animals to the human situation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Animals
  • Cell Count
  • Cytokines / metabolism*
  • Disease Models, Animal
  • Drug Antagonism
  • Drug Therapy, Combination
  • Emphysema / chemically induced
  • Emphysema / metabolism
  • Emphysema / pathology
  • Eosinophils / drug effects
  • Eosinophils / pathology
  • Female
  • Inhalation Exposure / adverse effects
  • Lung / drug effects*
  • Lung / metabolism
  • Lung / pathology
  • Mice
  • Mice, Inbred Strains
  • Nitrogen Dioxide / toxicity*
  • Pneumonia / chemically induced
  • Pneumonia / metabolism
  • Pneumonia / pathology
  • Smoke / adverse effects*
  • Smoking / adverse effects*
  • Tobacco*


  • Cytokines
  • Smoke
  • Nitrogen Dioxide