Role of platelet activating factor in kidney transplant rejection in the rat.
Platelet activating factor (PAF) is a potent lipid mediator with a broad range of biologic activities. Experimental evidence suggests that PAF plays a role in the pathogenesis of a variety of inflammatory processes including allograft rejection. In this study, we evaluated the effects of the PAF antagonist BN52021 on the course of renal allograft rejection in a rat model. Kidneys from ACI (RT1a) rats were transplanted into fully allogeneic PVG (RT1c) rat recipients. Animals received 60 mg/kg/day of the PAF antagonist or vehicle beginning immediately prior to the transplantation procedure. In rats treated with the PAF antagonist, allograft GFR and plasma flow were maintained at levels that were significantly greater than controls. Despite the improvement in renal allograft function, BN52021 had no effect on allograft histomorphology and both groups manifested intense inflammatory cell infiltration consistent with acute cellular rejection. PAF antagonism reduced urinary excretion of thromboxane metabolites and decreased thromboxane production by homogenates prepared from kidney allografts. The PAF antagonist had no effect on urinary excretion of peptidoleukotriene metabolites or on the production of LTB4 by allografts. These data support a role for PAF in the pathophysiology of acute renal allograft rejection, and they suggest that the hemodynamic effects of PAF during rejection may be mediated through stimulation of thromboxane A2. In view of the beneficial effects of PAF blockade in rejection as well as recent reports describing efficacy in models of cyclosporine nephrotoxicity, PAF antagonists may have clinical applications in human renal allograft recipients.
Butterly
D W
DW
Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Spurney
R F
RF
Ruiz
P
P
Pirotzky
E
E
Braquet
P
P
Coffman
T M
TM
D000818:Animals; D004224:Diterpenes; D046934:Ginkgolides; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006084:Graft Rejection / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016030:Kidney Transplantation; D007783:Lactones / Q000494:pharmacology; D017999:Leukotriene E4 / Q000652:urine; D008297:Male; D010936:Plant Extracts / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D011912:Rats, Inbred ACI; D011919:Rats, Inbred Strains; D012079:Renal Circulation / Q000187:drug effects; D013929:Thromboxane B2 / Q000096:biosynthesis
D004224:Diterpenes; D046934:Ginkgolides; D007783:Lactones; D010936:Plant Extracts; D010972:Platelet Activating Factor; D013929:Thromboxane B2; D017999:Leukotriene E4; C045856:ginkgolide B