title: Nitrogen dioxide induces apoptosis and proliferation but not emphysema in rat lungs.
abstract: BACKGROUND
  Apoptosis of alveolar septal cells has been linked to emphysema formation. Nitrogen dioxide, a component of cigarette smoke, has been shown to induce alveolar epithelial cell apoptosis in vitro. It is hypothesised that exposure of rats to nitrogen dioxide may result in increased alveolar septal cell apoptosis in vivo with ensuing emphysema-that is, airspace enlargement and loss of alveolar walls.
  
  
  METHODS
  Fischer 344 rats were exposed to 10 ppm nitrogen dioxide for 3, 7, 21 days or 21 days followed by 28 days at room air. Age-matched control rats were exposed to room air for 3, 21 or 49 days. Lungs fixed at 20 cm fluid column, embedded in paraffin wax, glycol methacrylate and araldite, were analysed by design-based stereology. Alveolar septal cell apoptosis (transferase dUTP nick end labelling assay, active caspase 3) and proliferation (Ki-67), airspace enlargement, total alveolar surface area, and absolute alveolar septal volume as well as the ultrastructural composition of the alveolar wall were quantified.
  
  
  RESULTS
  Nitrogen dioxide resulted in an eightfold increase in alveolar septal cell apoptosis at day 3 and a 14-fold increase in proliferation compared with age-matched controls. Airspace enlargement, indicated by a 20% increase in mean airspace chord length, was evident by day 7 but was not associated with loss of alveolar walls. By contrast, nitrogen dioxide resulted in an increase in the total surface area and absolute volume of alveolar walls comprising all compartments. The ratio of collagen to elastin, however, was reduced at day 21. Lungs exposed to nitrogen dioxide for 21 days exhibited quantitative structural characteristics as seen in control lungs on day 49.
  
  
  CONCLUSIONS
  Nitrogen dioxide exposure of rats results in increased alveolar septal cell turnover leading to accelerated lung growth, which is associated with an imbalance in the relative composition of the extracellular matrix, but fails to induce emphysema.
authors.affiliation: Clinical Research Group Chronic Airway Diseases, Department of Internal Medicine (Respiratory Medicine), Philipps University, Baldingerstrasse, D-35043 Marburg, Germany. heinz.fehrenbach@staff.uni-marburg.de
authors.forename: Heinz
authors.initials: H
authors.lastname: Fehrenbach
authors.forename: Gregor
authors.initials: G
authors.lastname: Zimmermann
authors.forename: Ellen
authors.initials: E
authors.lastname: Starke
authors.forename: Vlad A
authors.initials: VA
authors.lastname: Bratu
authors.forename: Dominik
authors.initials: D
authors.lastname: Conrad
authors.forename: Ali O
authors.initials: AO
authors.lastname: Yildirim
authors.forename: Antonia
authors.initials: A
authors.lastname: Fehrenbach
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D008297:Male; D008854:Microscopy, Electron; D009585:Nitrogen Dioxide / Q000494:pharmacology*; D011014:Pneumonia / Q000139:chemically induced; D011656:Pulmonary Emphysema / Q000139:chemically induced*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D009585:Nitrogen Dioxide