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. 1989 Jul;57(7):2196–2202. doi: 10.1128/iai.57.7.2196-2202.1989

Relationship between neutrophil-mediated oxidative injury during acute experimental pyelonephritis and chronic renal scarring.

P R Meylan 1, M Markert 1, J Bille 1, M P Glauser 1
PMCID: PMC313860  PMID: 2543635

Abstract

Previous experiments with rats have suggested that pyelonephritic scarring after acute ascending Escherichia coli pyelonephritis partly results from excessive polymorphonuclear leukocyte (PMN) infiltration and activation in the kidney parenchyma. We have studied the role of PMN oxidative metabolism in generating tissue injury during acute pyelonephritis. Rats with acute pyelonephritis were treated with dapsone (25 mg/kg twice daily for 3 days), a compound known to prevent PMN oxidant damage. In vitro, levels of dapsone easily achieved in vivo inhibited myeloperoxidase (MPO)-mediated reactions involving the oxidation of halides to reactive cytotoxic hypohalites (such as MPO-mediated iodination and luminol-enhanced chemiluminescence). In contrast, dapsone had no effect on superoxide production, lysosomal enzyme release, or bacterial killing by activated PMN. In vivo, dapsone treatment had no significant effect on acute pyelonephritis with respect to (i) bacterial counts, (ii) inflammatory swelling, and (iii) PMN infiltration. However, dapsone-treated animals sacrificed 2 months after acute pyelonephritis had a 65% reduction of renal scars when compared with controls. Since dapsone had no antibacterial effect, this protection is compatible with the hypothesis that dapsone prevented oxidant-generated tissue injury due to the extracellular release of the MPO system by activated PMN during acute suppurative pyelonephritis.

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Selected References

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  1. Anderson R., Gatner E. M., van Rensburg C. E., Grabow G., Imkamp F. M., Kok S. K., van Rensburg A. J. In vitro and in vivo effects of dapsone on neutrophil and lymphocyte functions in normal individuals and patients with lepromatous leprosy. Antimicrob Agents Chemother. 1981 Apr;19(4):495–503. doi: 10.1128/aac.19.4.495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Aniansson H., Stendahl O., Dahlgren C. Comparison between luminol- and lucigenindependent chemiluminescence of polymorphonuclear leukocytes. Acta Pathol Microbiol Immunol Scand C. 1984 Dec;92(6):357–361. doi: 10.1111/j.1699-0463.1984.tb00100.x. [DOI] [PubMed] [Google Scholar]
  3. Baehner R. L., Karnovsky M. J., Karnovsky M. L. Degranulation of leukocytes in chronic granulomatous disease. J Clin Invest. 1969 Jan;48(1):187–192. doi: 10.1172/JCI105967. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bainton D. F., Farquhar M. G. Differences in enzyme content of azurophil and specific granules of polymorphonuclear leukocytes. II. Cytochemistry and electron microscopy of bone marrow cells. J Cell Biol. 1968 Nov;39(2):299–317. doi: 10.1083/jcb.39.2.299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Baron E. J., Proctor R. A. Elicitation of peritoneal polymorphonuclear neutrophils from mice. J Immunol Methods. 1982 Mar 26;49(3):305–313. doi: 10.1016/0022-1759(82)90130-2. [DOI] [PubMed] [Google Scholar]
  6. Bille J., Glauser M. P. Protection against chronic pyelonephritis in rats by suppression of acute suppuration: effect of colchicine and neutropenia. J Infect Dis. 1982 Aug;146(2):220–226. doi: 10.1093/infdis/146.2.220. [DOI] [PubMed] [Google Scholar]
  7. Bradley P. P., Christensen R. D., Rothstein G. Cellular and extracellular myeloperoxidase in pyogenic inflammation. Blood. 1982 Sep;60(3):618–622. [PubMed] [Google Scholar]
  8. Brooks S. J., Lyons J. M., Braude A. I. Immunization against retrograde pyelonephritis. I. Production of an experimental model of severe ascending Escherichia coli pyelonephritis without bacteremia in rats. Am J Pathol. 1974 Feb;74(2):345–358. [PMC free article] [PubMed] [Google Scholar]
  9. Brooks S. J., Lyons J. M., Braude A. I. Immunization against retrograde pyelonephritis. II. Prevention of retrograde Escherichia coli pyelonephritis with vaccines. Am J Pathol. 1974 Feb;74(2):359–364. [PMC free article] [PubMed] [Google Scholar]
  10. Brooks S. J., Lyons J. M., Braude A. I. Immunization against retrograde pyelonephritis. III. Vaccination against chronic pyelonephritis due to Escherichia coli. J Infect Dis. 1977 Nov;136(5):633–639. doi: 10.1093/infdis/136.5.633. [DOI] [PubMed] [Google Scholar]
  11. CHANG Y. T., WOLCOTT R. R., DOULL J. A. Sulfone therapy of leprosy. Med Clin North Am. 1954 Mar;11:599–610. doi: 10.1016/s0025-7125(16)34902-1. [DOI] [PubMed] [Google Scholar]
  12. Clark R. A., Klebanoff S. J., Einstein A. B., Fefer A. Peroxidase-H2O2-halide system: Cytotoxic effect on mammalian tumor cells. Blood. 1975 Feb;45(2):161–170. [PubMed] [Google Scholar]
  13. Clark R. A., Klebanoff S. J. Myeloperoxidase--H2O2--halide system: cytotoxic effect on human blood leukocytes. Blood. 1977 Jul;50(1):65–70. [PubMed] [Google Scholar]
  14. Clark R. A., Klebanoff S. J. Myeloperoxidase-mediated platelet release reaction. J Clin Invest. 1979 Feb;63(2):177–183. doi: 10.1172/JCI109287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. 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]
  16. DeChatelet L. R., Long G. D., Shirley P. S., Bass D. A., Thomas M. J., Henderson F. W., Cohen M. S. Mechanism of the luminol-dependent chemiluminescence of human neutrophils. J Immunol. 1982 Oct;129(4):1589–1593. [PubMed] [Google Scholar]
  17. Esterly N. B., Furey N. L., Flanagan L. E. The effect of antimicrobial agents on leukocyte chemotaxis. J Invest Dermatol. 1978 Jan;70(1):51–55. doi: 10.1111/1523-1747.ep12543487. [DOI] [PubMed] [Google Scholar]
  18. Glauser M. P., Francioli P. B., Bille J., Bonard M., Meylan P. Effect of indomethacin on the incidence of experimental Escherichia coli pyelonephritis. Infect Immun. 1983 May;40(2):529–533. doi: 10.1128/iai.40.2.529-533.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Glauser M. P., Lyons J. M., Braude A. I. Prevention of chronic experimental pyelonephritis by suppression of acute suppuration. J Clin Invest. 1978 Feb;61(2):403–407. doi: 10.1172/JCI108951. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Henson P. M., Johnston R. B., Jr Tissue injury in inflammation. Oxidants, proteinases, and cationic proteins. J Clin Invest. 1987 Mar;79(3):669–674. doi: 10.1172/JCI112869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kazmierowski J. A., Ross J. E., Peizner D. S., Wuepper K. D. Dermatitis herpetiformis: effects of sulfones and sulfonamides on neutrophil myeloperoxidase-mediated iodination and cytotoxicity. J Clin Immunol. 1984 Jan;4(1):55–64. doi: 10.1007/BF00915288. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Klebanoff S. J. Myeloperoxidase: contribution to the microbicidal activity of intact leukocytes. Science. 1970 Sep 11;169(3950):1095–1097. doi: 10.1126/science.169.3950.1095. [DOI] [PubMed] [Google Scholar]
  24. Lang P. G., Jr Sulfones and sulfonamides in dermatology today. J Am Acad Dermatol. 1979 Dec;1(6):479–492. doi: 10.1016/s0190-9622(79)80088-2. [DOI] [PubMed] [Google Scholar]
  25. Lehrer R. I., Cline M. J. Leukocyte myeloperoxidase deficiency and disseminated candidiasis: the role of myeloperoxidase in resistance to Candida infection. J Clin Invest. 1969 Aug;48(8):1478–1488. doi: 10.1172/JCI106114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Markert M., Andrews P. C., Babior B. M. Measurement of O2- production by human neutrophils. The preparation and assay of NADPH oxidase-containing particles from human neutrophils. Methods Enzymol. 1984;105:358–365. doi: 10.1016/s0076-6879(84)05048-5. [DOI] [PubMed] [Google Scholar]
  27. Martin W. J., 2nd, Kachel D. L. Reduction of neutrophil-mediated injury to pulmonary endothelial cells by dapsone. Am Rev Respir Dis. 1985 Apr;131(4):544–547. doi: 10.1164/arrd.1985.131.4.544. [DOI] [PubMed] [Google Scholar]
  28. Meylan P. R., Glauser M. P. Failure of dexamethasone to prevent polymorphonuclear leukocyte infiltration during experimental acute exudative pyelonephritis and to reduce subsequent chronic scarring. J Infect Dis. 1988 Mar;157(3):480–485. doi: 10.1093/infdis/157.3.480. [DOI] [PubMed] [Google Scholar]
  29. Miller T., Phillips S. Pyelonephritis: the relationship between infection, renal scarring, and antimicrobial therapy. Kidney Int. 1981 May;19(5):654–662. doi: 10.1038/ki.1981.65. [DOI] [PubMed] [Google Scholar]
  30. Miyachi Y., Niwa Y. Effects of potassium iodide, colchicine and dapsone on the generation of polymorphonuclear leukocyte-derived oxygen intermediates. Br J Dermatol. 1982 Aug;107(2):209–214. doi: 10.1111/j.1365-2133.1982.tb00340.x. [DOI] [PubMed] [Google Scholar]
  31. Ransley P. G., Risdon R. A. Reflux nephropathy: effects of antimicrobial therapy on the evolution of the early pyelonephritic scar. Kidney Int. 1981 Dec;20(6):733–742. doi: 10.1038/ki.1981.204. [DOI] [PubMed] [Google Scholar]
  32. Roberts J. A., Domingue G. J., Martin L. N., Kim J. C. Immunology of pyelonephritis in the primate model: live versus heat-killed bacteria. Kidney Int. 1981 Feb;19(2):297–305. doi: 10.1038/ki.1981.20. [DOI] [PubMed] [Google Scholar]
  33. Roberts J. A., Roth J. K., Jr, Domingue G., Lewis R. W., Kaack B., Baskin G. Immunology of pyelonephritis in the primate model. V. Effect of superoxide dismutase. J Urol. 1982 Dec;128(6):1394–1400. doi: 10.1016/s0022-5347(17)53516-8. [DOI] [PubMed] [Google Scholar]
  34. Ruzicka T., Bauer A., Glück S., Born M. Effects of dapsone on passive Arthus reaction and chemotaxis and phagocytosis of polymorphonuclear leukocytes. Arch Dermatol Res. 1981;270(3):347–351. doi: 10.1007/BF00403939. [DOI] [PubMed] [Google Scholar]
  35. Slotki I. N., Asscher A. W. Prevention of scarring in experimental pyelonephritis in the rat by early antibiotic therapy. Nephron. 1982;30(3):262–268. doi: 10.1159/000182484. [DOI] [PubMed] [Google Scholar]
  36. Smith D. C., Klebanoff S. J. A uterine fluid-mediated sperm-inhibitory system. Biol Reprod. 1970 Oct;3(2):229–235. doi: 10.1093/biolreprod/3.2.229. [DOI] [PubMed] [Google Scholar]
  37. Stendahl O., Molin L., Dahlgren C. The inhibition of polymorphonuclear leukocyte cytotoxicity by dapsone. A possible mechanism in the treatment of dermatitis herpetiformis. J Clin Invest. 1978 Jul;62(1):214–220. doi: 10.1172/JCI109109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Thomas E. L., Grisham M. B., Jefferson M. M. Myeloperoxidase-dependent effect of amines on functions of isolated neutrophils. J Clin Invest. 1983 Aug;72(2):441–454. doi: 10.1172/JCI110992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Weiss S. J., Klein R., Slivka A., Wei M. Chlorination of taurine by human neutrophils. Evidence for hypochlorous acid generation. J Clin Invest. 1982 Sep;70(3):598–607. doi: 10.1172/JCI110652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Weissmann G., Smolen J. E., Korchak H. M. Release of inflammatory mediators from stimulated neutrophils. N Engl J Med. 1980 Jul 3;303(1):27–34. doi: 10.1056/NEJM198007033030109. [DOI] [PubMed] [Google Scholar]

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