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Nitrogen dioxide induces apoptosis and proliferation but not emphysema in rat lungs
  1. Heinz Fehrenbach (fehrenba{at}
  1. Philipps University, Germany
    1. Gregor Zimmermann (gs.zimmermann{at}
    1. Philipps University, Germany
      1. Ellen Starke (ellen.starke{at}
      1. Philipps University, Germany
        1. Vlad A Bratu (tony{at}
        1. Philipps University, Germany
          1. Dominik Conrad (sarig{at}
          1. Philipps University, Germany
            1. Ali Oender Yildirim (ayildiri{at}
            1. Philipps University, Germany
              1. Antonia Fehrenbach (antonia.fehrenbach{at}
              1. Philipps University, Germany


                Background: Apoptosis of alveolar septal cells has been linked to emphysema formation. Nitrogen dioxide, a component of cigarette smoke, was shown to induce alveolar epithelial cell apoptosis in vitro. We hypothesized that nitrogen dioxide exposure of rats may result in increased alveolar septal cell apoptosis in vivo with ensuing emphysema, i.e. 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 into paraffin, glycol methacrylate, and araldite were analyzed by design-based stereology. We quantified alveolar septal cell apoptosis (TUNEL 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.

                Results: Nitrogen dioxide resulted in 8-fold increase of alveolar septal cell apoptosis at day 3, and 14-fold increase in proliferation compared with age- matched controls. Airspace enlargement, indicated by 20% increase in mean airspace chord length, was evident by day 7, but was not associated with loss of alveolar walls. In contrast, nitrogen dioxide resulted in increased 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 seen in control lungs day 49.

                Conclusions: Nitrogen dioxide exposure of rats results in increased alveolar septal cell turnover leading to accelerated lung growth, which was associated with an imbalance in the relative composition of the extracellular matrix, but fails to induce emphysema.

                • airspace enlargement
                • apoptosis
                • emphysema
                • nitrogen dioxide
                • proliferation

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