Classical and alternative macrophage activation in the lung following ozone-induced oxidative stress

Toxicol Appl Pharmacol. 2012 Sep 1;263(2):195-202. doi: 10.1016/j.taap.2012.06.009. Epub 2012 Jun 19.


Ozone is a pulmonary irritant known to cause oxidative stress, inflammation and tissue injury. Evidence suggests that macrophages play a role in the pathogenic response; however, their contribution depends on the mediators they encounter in the lung which dictate their function. In these studies we analyzed the effects of ozone-induced oxidative stress on the phenotype of alveolar macrophages (AM). Exposure of rats to ozone (2 ppm, 3h) resulted in increased expression of 8-hydroxy-2'-deoxyguanosine (8-OHdG), as well as heme oxygenase-1 (HO-1) in AM. Whereas 8-OHdG was maximum at 24h, expression of HO-1 was biphasic increasing after 3h and 48-72 h. Cleaved caspase-9 and beclin-1, markers of apoptosis and autophagy, were also induced in AM 24h post-ozone. This was associated with increased bronchoalveolar lavage protein and cells, as well as matrix metalloproteinase (MMP)-2 and MMP-9, demonstrating alveolar epithelial injury. Ozone intoxication resulted in biphasic activation of the transcription factor, NFκB. This correlated with expression of monocyte chemotactic protein-1, inducible nitric oxide synthase and cyclooxygenase-2, markers of proinflammatory macrophages. Increases in arginase-1, Ym1 and galectin-3 positive anti-inflammatory/wound repair macrophages were also observed in the lung after ozone inhalation, beginning at 24h (arginase-1, Ym1), and persisting for 72 h (galectin-3). This was associated with increased expression of pro-surfactant protein-C, a marker of Type II cell proliferation and activation, important steps in wound repair. These data suggest that both proinflammatory/cytotoxic and anti-inflammatory/wound repair macrophages are activated early in the response to ozone-induced oxidative stress and tissue injury.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 8-Hydroxy-2'-Deoxyguanosine
  • Animals
  • Apoptosis / drug effects
  • Autophagy / drug effects
  • Cell Proliferation / drug effects
  • Deoxyguanosine / analogs & derivatives
  • Deoxyguanosine / genetics
  • Female
  • Gene Expression Regulation / drug effects*
  • Heme Oxygenase-1 / genetics
  • Inflammation / chemically induced
  • Inflammation / pathology
  • Lung / drug effects*
  • Lung / pathology
  • Macrophages, Alveolar / drug effects*
  • Macrophages, Alveolar / pathology
  • Oxidative Stress / drug effects*
  • Ozone / administration & dosage
  • Ozone / toxicity
  • Protein C / genetics
  • Rats
  • Rats, Wistar
  • Time Factors


  • Protein C
  • Ozone
  • 8-Hydroxy-2'-Deoxyguanosine
  • Heme Oxygenase-1
  • Deoxyguanosine