Pharmacological manipulation of inflammation in rabbit hydronephrosis: effects of a combined cyclooxygenase/lipoxygenase inhibitor ethoxyquin, a thromboxane synthase inhibitor RS-5186 and a PAF antagonist L-659,989.
The rabbit hydronephrotic kidney (HNK) is a model of renal inflammation characterized by a marked increase in arachidonic acid metabolism that is temporally associated with an inflammatory cell influx into the injured tissue. The HNK exhibits an exaggerated elaboration of eicosanoids ex vivo in response to either bradykinin or the inflammatory cell agonist n-formyl-methionyl-leucyl-phenylalanine (fMLP) compared with the unobstructed contralateral kidney. To pharmacologically manipulate inflammatory cell influx into the HNK we administered ethoxyquin (200 mg/kg p.o.), a combined cyclooxygenase/lipoxygenase inhibitor, RS-5186 (10 mg/kg p.o.), a thromboxane synthase inhibitor or L-659,989 (5 mg/kg p.o.), a platelet activating factor antagonist, before and at various times during the development of hydronephrosis. Only ethoxyquin reduced inflammatory cell influx into the HNK and thereby prevented the enhancement of microsomal cyclooxygenase activity and attenuated the elaboration of eicosanoids ex vivo. Collectively, these results suggest a primary role of an eicosanoid, possibly leukotriene B4, but not thromboxane A2 or the chemotactic phospholipid, platelet activating factor, as a mediator of inflammatory cell influx resulting from ureter obstruction.
Spaethe
S M
SM
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana.
Hsueh
W
W
Needleman
P
P
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors; D005015:Ethoxyquin / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000172:deficiency; D005663:Furans / Q000494:pharmacology*; D006869:Hydronephrosis / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007975:Leukotriene B4 / Q000502:physiology; D016859:Lipoxygenase Inhibitors; D008297:Male; D010477:Perfusion; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000494:pharmacology*; D011817:Rabbits; D013876:Thiophenes / Q000494:pharmacology*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D005230:Fatty Acids, Nonesterified; D005663:Furans; D016859:Lipoxygenase Inhibitors; D010972:Platelet Activating Factor; D011804:Quinolines; D013876:Thiophenes; C055806:RS 5186; C054893:L 659989; D007975:Leukotriene B4; D016718:Arachidonic Acid; D005015:Ethoxyquin; D013930:Thromboxane-A Synthase