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Relationship between neutrophil-mediated oxidative injury during acute experimental pyelonephritis and chronic renal
P R Meylan1, M Markert, J Bille
1Département de Médecine Interne, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
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.
Insights
Dapsone treatment reduced kidney scarring in rats with pyelonephritis by inhibiting polymorphonuclear leukocyte (PMN) oxidative damage. This suggests PMN myeloperoxidase (MPO) activity contributes to renal scarring.
Area of Science:
- Nephrology
- Immunology
- Pharmacology
Background:
- Pyelonephritic scarring in rats is linked to polymorphonuclear leukocyte (PMN) infiltration and activation.
- The role of PMN oxidative metabolism in kidney tissue injury during acute pyelonephritis requires further investigation.
Purpose of the Study:
- To investigate the role of PMN oxidative metabolism in generating tissue injury during acute pyelonephritis.
- To evaluate the therapeutic potential of dapsone in preventing renal scarring.
Main Methods:
- Rats with acute pyelonephritis were treated with dapsone, an inhibitor of PMN oxidant damage.
- In vitro studies assessed dapsone's effect on PMN myeloperoxidase (MPO)-mediated reactions.
- In vivo efficacy was evaluated by measuring bacterial counts, swelling, PMN infiltration, and renal scarring after 2 months.
Main Results:
- Dapsone inhibited in vitro MPO-mediated reactions but did not affect superoxide production, lysosomal enzyme release, or bacterial killing by PMN.
- In vivo, dapsone treatment did not alter bacterial counts, inflammatory swelling, or PMN infiltration.
- Dapsone-treated rats showed a 65% reduction in renal scars compared to controls.
Conclusions:
- Dapsone's protective effect against renal scarring is likely due to the inhibition of PMN MPO-mediated oxidant damage.
- This suggests that PMN oxidative metabolism contributes significantly to tissue injury and scarring in pyelonephritis.