In this study, the relationship between leukotrienes, peritubular cell infiltration with polymorphonuclear cells (PMNs) and renal tubular damage was investigated in a rat model of acute ascending pyelonephritis.Infection was induced by the injection of 105 CFU of Escherichia coli into the bladder and occlusion of the left ureter for 24 h. Treatment of infected animals was started 24 h after the induction of pyelonephritis with either hydrocortisone (25 mg/kg of body weight per day), the leukotriene inhibitor L-651,392 (10 mg/kg/day), or the vehicle of L-651,392 and was maintained for 5 days. At the end of treatment, the animals were killed, serum was collected, and both kidneys were removed for colony counts and histopathology. Renal function was evaluated by the measurement of blood urea nitrogen levels and creatinine clearance. The numbers of PMNs and mononuclear cells (MNs) in the cortex and medulla were recorded for all groups on plastic sections done from the left kidney. Infection alone (vehicle of L-651,392) resulted in intensive interstitial infiltration and a severe tubular destruction in the cortex. Treatment with hydrocortisone did not prevent PMN migration and tissue damage. By contrast, treatment with L-651,392 resulted in a significant reduction in PMNs (P < 0.001 in comparisons with all other groups) and greater preservation of the tubular structure despite identical bacterial counts than in the group receiving hydrocortisone. We conclude that L-651,392 prevents inflammatory cells from reaching the site of infection and protects the kidney from tubular damage associated with inflammation during pyelonephritis. Inhibitors of leukotrienes should be further investigated for their potential benefit as adjuvants to antibiotherapy in the treatment of pyelonephritis.Several studies support the hypothesis that acute inflammation plays a major role in the development of tissue damage during infection. For example (17,37), the presence of bacteria in the renal parenchyma during pyelonephritis induces a marked local cellular and humoral response. Inflammatory cells such as polymorphonuclear cells (PMNs) migrate into the interstitium under chemotactic stimuli and then release free oxygen radicals (02 -, OH, and H202) and lysosomal enzymes into their environment. Although these products are essential for bacterial killing, they are in part responsible for deleterious effects to host cells, including tissue damage and scar formation, with the ensuing decreased renal function as well as permanent kidney damage.While the C5a fraction of complement may initiate the migration of PMNs in the early phase of the infection (38), the potent chemotactic leukotriene B4 (LTB4) and also the cysteinyl leukotrienes LTC4, -D4, and -E4 are suspected of playing an important role in the outcome of pyelonephritis. Infiltrating leukocytes and cells from the rat glomeruli can produce leukotrienes (2, 11). Their synthesis is stimulated by bacterial components such as endotoxin. Studies of septic shock and different diseases of the lu...