Lipid-derived free radical production in superantigen-induced interstitial pneumonia.
We studied the free radical generation involved in the development of interstitial pneumonia (IP) in an animal model of autoimmune disease. We observed an electron spin resonance (ESR) spectrum of alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN) radical adducts detected in the lipid extract of lungs in autoimmune-prone mice after intratracheal instillation of staphylococcal enterotoxin B. The POBN adducts detected by ESR were paralleled by infiltration of macrophages and neutrophils into the bronchoalveolar lavage fluid. To further investigate the mechanism of free radical generation, mice were pretreated with the macrophage toxicant gadolinium chloride, which significantly suppressed the radical generation. Free radical generation was also decreased by pretreatment with the xanthine oxidase (XO) inhibitor allopurinol, the iron chelator Desferal, and the inducible nitric oxide synthase (iNOS) inhibitor 1400W. Histopathologically, these drugs significantly reduced both the cell infiltration into the alveolar septal walls and the synthesis of pulmonary collagen fibers. Experiments with NADPH oxidase knockout mice showed that NADPH oxidase did not contribute to lipid radical generation. These results suggest that lipid-derived carbon-centered free radical production is important in the manifestation of IP and that a macrophage toxicant, an XO inhibitor, an iron chelator, and an iNOS inhibitor protect against both radical generation and the manifestation of IP.
Miyakawa
Hisako
H
Free Radical Metabolite Section, Laboratory of Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Mason
Ronald P
RP
Jiang
Jinjie
J
Kadiiska
Maria B
MB
D000493:Allopurinol / Q000494:pharmacology; D000578:Amidines / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D003676:Deferoxamine / Q000494:pharmacology; D004578:Electron Spin Resonance Spectroscopy; D004768:Enterotoxins / Q000008:administration & dosage; D005260:Female; D005682:Gadolinium / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000494:pharmacology; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D017563:Lung Diseases, Interstitial / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D018384:Oxidative Stress / Q000187:drug effects; D011725:Pyridines / Q000378:metabolism*; D018089:Superantigens / Q000276:immunology / Q000378:metabolism; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors
C450079:(pyridyl-4-N-oxide)-N-tert-butylnitrone; D000578:Amidines; D000893:Anti-Inflammatory Agents; D001596:Benzylamines; D004768:Enterotoxins; D007502:Iron Chelating Agents; D008562:Membrane Glycoproteins; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D011725:Pyridines; D018089:Superantigens; C031818:enterotoxin B, staphylococcal; D000493:Allopurinol; D005682:Gadolinium; D019001:Nitric Oxide Synthase; D014969:Xanthine Oxidase; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D003676:Deferoxamine; C038958:gadolinium chloride