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Shift Toward an Alternatively Activated Macrophage Response in Lungs of NO₂-Exposed Rats

Institute of Immunology, Department of Pathology, and Department of Internal Medicine, Laboratory of Lung Cell Biology, Philipps University Marburg, Marburg, Germany

Address correspondence to: Dr. Holger Garn, Institute of Immunology, Philipps University Marburg, Robert-Koch-Str. 17, D-35037 Marburg, Germany. E-mail: garn{at}mailer.uni-marburg.de

Inflammatory mechanisms are thought to play an important role in the pathogenesis of acute and chronic obstructive pulmonary diseases. In a rat inhalation model using continuous exposure to 10 ppm nitrogen dioxide for 1, 3, and 20 d, we investigated the inflammatory response with particular focus on the activation state of alveolar macrophages. Whereas the number of inflammatory cells and total protein concentration were increased in the bronchoalveolar lavage (BAL), the amount of the proinflammatory cytokine tumor necrosis factor- was markedly reduced with increasing exposure time. In contrast, interleukin (IL)-10 and IL-6 were found at elevated levels and intracellular amounts of suppressor of cytokine signaling-3 protein increased in BAL cells. Upon in vitro lipopolysaccharide stimulation, BAL cells revealed reduced capability to produce the proinflammatory mediators tumor necrosis factor-, IL-1ß, and nitric oxide, but showed markedly increased transcription and protein release for IL-10. In addition, elevated levels of IL-6, scavenger receptor B, and suppressor of cytokine signaling-3 mRNA were detected in BAL cells from exposed animals. Analyses of highly purified alveolar macrophages indicated that changes in the activation state of these cells were responsible for the observed effects. In conclusion, a priming toward development of the alternatively activated macrophage phenotype occurred in the lungs of rats following nitrogen dioxide inhalation.

Abbreviations: alveolar macrophages, AMs • bronchoalveolar lavage, BAL • chronic obstructive pulmonary disease, COPD • enzyme-linked immunosorbent assay, ELISA • fluorescence-activated cell sorter, FACS • fetal calf serum, FCS • fluorescein isothiocyanate, FITC • hematoxylin and eosin, H&E • interferon-, IFN- • interleukin, IL • lipopolysaccharide, LPS • phosphate-buffered saline, PBS • phycoerythrin, PE • reverse transcriptase–polymerase chain reaction, RT-PCR • suppressor of cytokine signaling, SOCS • scavenger receptor B, SR-B • transforming growth factor-ß, TGF-ß • tumor necrosis factor-, TNF-

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