NO2-induced airway inflammation is associated with progressive airflow limitation and development of emphysema-like lesions in C57bl/6 mice

Exp Toxicol Pathol. 2005 Apr;56(6):341-50. doi: 10.1016/j.etp.2004.12.004.


The major features of chronic obstructive pulmonary disease (COPD) comprise a not fully reversible airflow limitation associated with an abnormal inflammatory response, increased mucus production and development of emphysema-like lesions. Animal models that closely mimic these alterations represent an important issue for the investigation of pathophysiological mechanisms. Since most animal models in this area have focused on specific aspects of the disease, we aimed to investigate whether exposure of C57BL/6 mice to nitrogen dioxide (NO2) may cause a more complex phenotype covering several of the characteristics of the human disease. Therefore, mice were exposed to NO2 for 14h each day for up to 25 days. Initial dose response experiments revealed the induction of a significant inflammatory response at a dose of 20 ppm NO2. Mice developed progressive airway inflammation together with a focal inflammation of the lung parenchyma characterized by a predominant influx of neutrophils and macrophages. In addition, goblet cell hyperplasia was detected in the central airways and increased collagen deposition was found in the lung parenchyma. NO2-exposed mice developed emphysema-like lesions as indicated by a significantly increased mean linear intercept as compared to control mice. Finally, the assessment of lung functional parameters revealed the development of progressive airway obstruction over time. In conclusion, our data provide evidence that the inflammatory response to NO2 exposure is associated with increased mucus production, development of airspace enlargement and progressive airway obstruction. Thus, NO2-exposed mice may serve as a model to investigate pathophysiological mechanisms that contribute to the development of human COPD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bronchitis, Chronic / chemically induced*
  • Bronchitis, Chronic / pathology
  • Bronchitis, Chronic / physiopathology
  • Bronchoalveolar Lavage Fluid / cytology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Emphysema / chemically induced*
  • Emphysema / pathology
  • Emphysema / physiopathology
  • Leukocyte Count
  • Lung / drug effects
  • Lung / pathology
  • Lung / physiopathology
  • Macrophages, Alveolar / drug effects
  • Macrophages, Alveolar / pathology
  • Mice
  • Mice, Inbred C57BL
  • Neutrophils / drug effects
  • Neutrophils / pathology
  • Nitrogen Dioxide / toxicity*
  • Oxidants, Photochemical / toxicity*
  • Pulmonary Disease, Chronic Obstructive / chemically induced*
  • Pulmonary Disease, Chronic Obstructive / pathology
  • Pulmonary Disease, Chronic Obstructive / physiopathology
  • Pulmonary Ventilation / drug effects
  • Pulmonary Ventilation / physiology
  • Specific Pathogen-Free Organisms


  • Oxidants, Photochemical
  • Nitrogen Dioxide