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. 1981 Apr;67(4):983–993. doi: 10.1172/JCI110149

In vivo damage of rat lungs by oxygen metabolites.

K J Johnson, J C Fantone 3rd, J Kaplan, P A Ward
PMCID: PMC370656  PMID: 6894154

Abstract

The intrapulmonary instillation into rat lung of enzymes that generate oxygen metabolites results in acute lung injury. The injection of xanthine oxidase and xanthine produces acute lung injury that, in the presence of superoxide dismutase, but not in the presence of catalase, can be significantly diminished, suggesting that O2- has the capacity to injure the lung. Instillation of a generator of H2O2, namely glucose oxidase, will, in sufficient quantities, produce acute injury that is not neutrophil-dependent. When either a low dose of glucose oxidase alone or lactoperoxidase alone is employed, little lung injury occurs. However, instilling the combination of the two enzymes produces severe, acute injury that can be blocked in a dose-dependent manner by catalase, but not by superoxide dismutase. Purified human leukocytic myeloperoxidase, but not horseradish peroxidase, will substitute for lactoperoxidase in the model of lung injury. The lung damaging effects of these enzymes cannot be attributed to the presence of contaminating proteases. Acute lung injury produced by the instillation of glucose oxidase and lactoperioxidase progresses to interstitial fibrosis. These studies represent a direct application of generators of oxygen metabolites to the in vivo induction of lung injury. The data suggest that rat lung is susceptible to injury by a variety of oxygen metabolites, including O2-, H2O2 and its lactoperoxidase or myeloperoxidase-produced derivatives. The studies also indicate that lung injury produced by oxygen metabolites can result in interstitial pulmonary fibrosis.

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Selected References

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  1. BEERS R. F., Jr, SIZER I. W. A spectrophotometric method for measuring the breakdown of hydrogen peroxide by catalase. J Biol Chem. 1952 Mar;195(1):133–140. [PubMed] [Google Scholar]
  2. Becker E. L., Sigman M., Oliver J. M. Superoxide production induced in rabbit polymorphonuclear leukocytes by synthetic chemotactic peptides and A23187. Am J Pathol. 1979 Apr;95(1):81–97. [PMC free article] [PubMed] [Google Scholar]
  3. Burk R. F., Lawrence R. A., Lane J. M. Liver necrosis and lipid peroxidation in the rat as the result of paraquat and diquat administration. Effect of selenium deficiency. J Clin Invest. 1980 May;65(5):1024–1031. doi: 10.1172/JCI109754. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Clark R. A., Klebanoff S. J. Neutrophil-mediated tumor cell cytotoxicity: role of the peroxidase system. J Exp Med. 1975 Jun 1;141(6):1442–1447. doi: 10.1084/jem.141.6.1442. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Curnutte J. T., Babior B. M. Biological defense mechanisms. The effect of bacteria and serum on superoxide production by granulocytes. J Clin Invest. 1974 Jun;53(6):1662–1672. doi: 10.1172/JCI107717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Desai U., Kreutzer D. L., Showell H., Arroyave C. V., Ward P. A. Acute inflammatory pulmonary reactions induced by chemotactic factors. Am J Pathol. 1979 Jul;96(1):71–83. [PMC free article] [PubMed] [Google Scholar]
  7. Doroshow J. H., Locker G. Y., Myers C. E. Enzymatic defenses of the mouse heart against reactive oxygen metabolites: alterations produced by doxorubicin. J Clin Invest. 1980 Jan;65(1):128–135. doi: 10.1172/JCI109642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hafeman D. G., Lucas Z. J. Polymorphonuclear leukocyte-mediated, antibody-dependent, cellular cytotoxicity against tumor cells: dependence on oxygen and the respiratory burst. J Immunol. 1979 Jul;123(1):55–62. [PubMed] [Google Scholar]
  9. Hunninghake G. W., Gadek J. E., Kawanami O., Ferrans V. J., Crystal R. G. Inflammatory and immune processes in the human lung in health and disease: evaluation by bronchoalveolar lavage. Am J Pathol. 1979 Oct;97(1):149–206. [PMC free article] [PubMed] [Google Scholar]
  10. Janoff A., White R., Carp H., Harel S., Dearing R., Lee D. Lung injury induced by leukocytic proteases. Am J Pathol. 1979 Oct;97(1):111–136. [PMC free article] [PubMed] [Google Scholar]
  11. Johnson K. J., Varani J., Oliver J., Ward P. A. Immunologic vasculitis in beige mice with deficiency of leukocytic neutral protease. J Immunol. 1979 May;122(5):1807–1811. [PubMed] [Google Scholar]
  12. Johnson K. J., Ward P. A. Acute immunologic pulmonary alveolitis. J Clin Invest. 1974 Aug;54(2):349–357. doi: 10.1172/JCI107770. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kellogg E. W., 3rd, Fridovich I. Liposome oxidation and erythrocyte lysis by enzymically generated superoxide and hydrogen peroxide. J Biol Chem. 1977 Oct 10;252(19):6721–6728. [PubMed] [Google Scholar]
  14. Klebanoff S. J. Antimicrobial mechanisms in neutrophilic polymorphonuclear leukocytes. Semin Hematol. 1975 Apr;12(2):117–142. [PubMed] [Google Scholar]
  15. Klebanoff S. J., Clark R. A. Hemolysis and iodination of erythrocyte components by a myeloperoxidase-mediated system. Blood. 1975 May;45(5):699–707. [PubMed] [Google Scholar]
  16. Lynch R. E., Fridovich I. Effects of superoxide on the erythrocyte membrane. J Biol Chem. 1978 Mar 25;253(6):1838–1845. [PubMed] [Google Scholar]
  17. Nathan C. F., Silverstein S. C., Brukner L. H., Cohn Z. A. Extracellular cytolysis by activated macrophages and granulocytes. II. Hydrogen peroxide as a mediator of cytotoxicity. J Exp Med. 1979 Jan 1;149(1):100–113. doi: 10.1084/jem.149.1.100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Petrone W. F., English D. K., Wong K., McCord J. M. Free radicals and inflammation: superoxide-dependent activation of a neutrophil chemotactic factor in plasma. Proc Natl Acad Sci U S A. 1980 Feb;77(2):1159–1163. doi: 10.1073/pnas.77.2.1159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Rister M., Baehner R. L. The alteration of superoxide dismutase, catalase, glutathione peroxidase, and NAD(P)H cytochrome c reductase in guinea pig polymorphonuclear leukocytes and alveolar macrophages during hyperoxia. J Clin Invest. 1976 Nov;58(5):1174–1184. doi: 10.1172/JCI108570. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Root R. K., Metcalf J., Oshino N., Chance B. H2O2 release from human granulocytes during phagocytosis. I. Documentation, quantitation, and some regulating factors. J Clin Invest. 1975 May;55(5):945–955. doi: 10.1172/JCI108024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Rosen H., Klebanoff S. J. Formation of singlet oxygen by the myeloperoxidase-mediated antimicrobial system. J Biol Chem. 1977 Jul 25;252(14):4803–4810. [PubMed] [Google Scholar]
  22. Rosen H., Klebanoff S. J. Hydroxyl radical generation by polymorphonuclear leukocytes measured by electron spin resonance spectroscopy. J Clin Invest. 1979 Dec;64(6):1725–1729. doi: 10.1172/JCI109637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Sacks T., Moldow C. F., Craddock P. R., Bowers T. K., Jacob H. S. Oxygen radicals mediate endothelial cell damage by complement-stimulated granulocytes. An in vitro model of immune vascular damage. J Clin Invest. 1978 May;61(5):1161–1167. doi: 10.1172/JCI109031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Salin M. L., McCord J. M. Superoxide dismutases in polymorphonuclear leukocytes. J Clin Invest. 1974 Oct;54(4):1005–1009. doi: 10.1172/JCI107816. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Saltzman H. A., Fridovich I. Editorial: Oxygen toxicity. Introduction to a protective enzyme: superoxide dismutase. Circulation. 1973 Nov;48(5):921–923. doi: 10.1161/01.cir.48.5.921. [DOI] [PubMed] [Google Scholar]
  26. Thorne K. J., Svvennsen R. J., Franks D. Role of hydrogen peroxide in the cytotoxic reaction of T lymphocytes. Clin Exp Immunol. 1980 Feb;39(2):486–495. [PMC free article] [PubMed] [Google Scholar]
  27. Thurman R. G., Ley H. G., Scholz R. Hepatic microsomal ethanol oxidation. Hydrogen peroxide formation and the role of catalase. Eur J Biochem. 1972 Feb;25(3):420–430. doi: 10.1111/j.1432-1033.1972.tb01711.x. [DOI] [PubMed] [Google Scholar]
  28. Weiss S. J., LoBuglio A. F., Kessler H. B. Oxidative mechanisms of monocyte-mediated cytotoxicity. Proc Natl Acad Sci U S A. 1980 Jan;77(1):584–587. doi: 10.1073/pnas.77.1.584. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Weiss S. J., Rustagi P. K., LoBuglio A. F. Human granulocyte generation of hydroxyl radical. J Exp Med. 1978 Feb 1;147(2):316–323. doi: 10.1084/jem.147.2.316. [DOI] [PMC free article] [PubMed] [Google Scholar]

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