Paradoxical exacerbation of leukocyte-mediated glomerulonephritis with cyclooxygenase inhibition.
Nephrotoxic nephritis (NTN) is characterized by glomerular inflammation, an increase in glomerular eicosanoid synthesis, and renal dysfunction. Data further suggest that eicosanoids may play a critical role in the inflammatory response. In the current study, we examined the effects of in vivo manipulation of arachidonate metabolism on the cellular component of the inflammatory response in NTN. We found that inhibition of cyclooxygenase with indomethacin in mild NTN caused a two- to fourfold increase in the leukocyte influx into glomeruli with a change histologically from a focal to a more diffuse lesion. Both the accompanying proteinuria and the increase in ex vivo glomerular eicosanoid production were also augmented by the administration of indomethacin. The effect of indomethacin was reversible and not limited to the acute phase of NTN. The administration of aspirin, like indomethacin, augmented the glomerular inflammation of NTN. Neither OKY-046 (a thromboxane synthase inhibitor) nor MK-886 (a 5-lipoxygenase inhibitor) altered the glomerular inflammation of NTN. Administration of exogenous prostaglandin E (in the form of misoprostol) did diminish the proteinuria accompanying NTN; however, glomerular inflammation was not significantly affected. Incubation of glomeruli with [14C]arachidonate demonstrated the presence of noncyclooxygenase pathways of arachidonate metabolism (11-, 12-, and 15-lipoxygenases) with increased activity in NTN. These data demonstrate that cyclooxygenase inhibition may paradoxically worsen glomerular inflammation and suggest a potential role for noncyclooxygenase/non-5-lipoxygenase pathways of arachidonate metabolism.
Nagamatsu
T
T
Department of Medicine, School of Medicine, Washington University, St. Louis, Missouri 63110.
Pippin
J
J
Schreiner
G F
GF
Lefkowith
J B
JB
D000818:Animals; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors; D002465:Cell Movement / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D005921:Glomerulonephritis / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D007213:Indomethacin / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000378:metabolism; D007700:Kinetics; D007962:Leukocytes / Q000502:physiology*; D011458:Prostaglandins E / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew
D016861:Cyclooxygenase Inhibitors; D011458:Prostaglandins E; D016718:Arachidonic Acid; D007213:Indomethacin