Renal microthrombosis following endotoxin infusion may be mediated by lipoxygenase products.
Renal microvascular thrombosis following endotoxin infusion was assessed by measuring accumulation of 125I-labeled fibrinogen and transmission electron microscopy. Endotoxin shock was induced in unanesthetized Sprague-Dawley rats using 14 mg/kg Escherichia coli endotoxin (Difco) infused intravenously over a 5-hour period. Fifteen minutes after infusion of endotoxin was started, intravenous treatment was initiated. Two-thirds of the treatment was given over a period of 20 minutes followed by the remaining dose over the next 2 hours. Five rats received methyl prednisolone sodium succinate (Solu-Medrol) (U-9,088) (39.5 mg/kg). Six rats received a Solu-Medrol analog (methyl prednisolone 21(N-Methyltaurosuberate), sodium salt) (U-67,590A) (61.08 mg/kg). Six rats received a 5-lipoxygenase inhibitor (1-naphthalenol,2,3,diethyl-4-methoxy-acetate) (U-66,855) (20 mg/kg). Six rats received a prostacyclin analog (pentanoic acid, 5- less than hexahydro-5-hydroxy-6-(3-hydroxy-1-octenyl)-3a-methyl-2(1H)- pentalenylidene greater than -calcium salt, hydrate) (U-61,431F) (0.04 mg/kg). Six rats received a thromboxane synthase inhibitor (2-benzofurancarboxylic acid, 5-(3-pyridinylmethyl), sodium salt monohydrate) (U-63,557A) (18 mg/kg). Eight endotoxin-infused rats received only normal saline. Six control rats received no endotoxin infusion, only saline. Composition and location of thrombi were assessed by transmission electron microscopy. Glomerular thrombosis was quantitated by determination of whole blood equivalents of 125I fibrin/g of tissue. Electron microscopy and radioactive quantitation demonstrated microthrombosis in the nontreated endotoxin group. The thrombi contained fibrin, platelets, erythrocytes, and leukocytes. The extent of thrombosis was significantly elevated compared to saline-treated controls. Three treated groups (U-9,088, U-67,590A, and U-66,855) all had significantly less thrombosis than the nontreated endotoxin rats. Two treated groups (U-63,557A and U-61,431F) developed glomerular thrombosis similar to untreated endotoxin rats. The results suggest that endotoxin stimulation of procoagulant activity and microthrombosis may be mediated by production of arachidonic acid metabolites via the lipoxygenase pathway.