Relationship between neutrophil-mediated oxidative injury during acute experimental pyelonephritis and chronic renal scarring.
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.
Meylan
P R
PR
Département de Médecine Interne, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Markert
M
M
Bille
J
J
Glauser
M P
MP
D000208:Acute Disease; D000818:Animals; D002908:Chronic Disease; D002921:Cicatrix / Q000188:drug therapy / Q000382:microbiology / Q000473:pathology*; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000378:metabolism; D003622:Dapsone / Q000008:administration & dosage / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects; D005609:Free Radicals; D006131:Growth Inhibitors / Q000494:pharmacology; D008297:Male; D009504:Neutrophils / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D010100:Oxygen / Q000633:toxicity*; D009195:Peroxidase / Q000502:physiology; D011704:Pyelonephritis / Q000188:drug therapy / Q000382:microbiology / Q000473:pathology*; D051381:Rats; D011919:Rats, Inbred Strains; D013481:Superoxides / Q000097:blood
D005609:Free Radicals; D006131:Growth Inhibitors; D013481:Superoxides; D003622:Dapsone; D009195:Peroxidase; D010100:Oxygen