Classical and alternative macrophage activation in the lung following ozone-induced oxidative stress.
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.
Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ 08854, USA. sunilva@pharmacy.rutgers.edu
Vasanthi R
VR
Sunil
Kinal
K
Patel-Vayas
Jianliang
J
Shen
Jeffrey D
JD
Laskin
Debra L
DL
Laskin
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D051547:Heme Oxygenase-1 / Q000235:genetics; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D010126:Ozone / Q000008:administration & dosage / Q000633:toxicity; D011486:Protein C / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D011486:Protein C; D010126:Ozone; D000080242:8-Hydroxy-2'-Deoxyguanosine; D051547:Heme Oxygenase-1; D003849:Deoxyguanosine