title: Prolongation of pig-to-dog renal xenograft survival by modification of the inflammatory mediator response.
abstract: The pathogenesis of hyperacute renal rejection consists of a nonspecific effector cascade that invokes most of the components of a typical acute inflammatory response. Platelet-activating factor (PAF) represents the most recent and perhaps the most significant mediator and promoting agent of this phenomenon. These studies evaluated SRI 63-441, a novel, synthetic, and the most potent PAF receptor antagonist available, alone and in combination with other prostanoids, for their ability to influence this response and to prolong renal xenograft survival and function in a model of pig-to-dog heterotransplantation. Inhibition of PAF by SRI 63-441 alone, at the dosage and schedule used in these experiments, did not significantly prolong xenograft survival or function. However, the combination of SRI 63-441 with either prostacyclin (PGI2) or prostaglandin E1 (PGE1) infusion demonstrated significant synergism, and resulted in a 6-9-fold increase in kidney survival and a 3-20-fold increase in urine output. Neither PGI2 nor PGE1 infusions alone significantly influenced this xenograft model. Electromagnetic flow studies demonstrated significantly delayed diminution in renal artery blood flow in the combination-treated animals. Serial and end-stage histologic examination of kidneys receiving combination therapy demonstrated a delayed onset of the pathologic deterioration and an overall amelioration of the entire process. These studies demonstrate that significant abrogation of a rapid and violent form of hyperacute rejection can be achieved solely by the pharmacologic manipulation of the inflammatory mediator response.
authors.affiliation: Department of Surgery, University Health Center of Pittsburgh, University of Pittsburgh, Pennsylvania.
authors.forename: L
authors.initials: L
authors.lastname: Makowka
authors.forename: C
authors.initials: C
authors.lastname: Miller
authors.forename: P
authors.initials: P
authors.lastname: Chapchap
authors.forename: L
authors.initials: L
authors.lastname: Podesta
authors.forename: C
authors.initials: C
authors.lastname: Pan
authors.forename: D
authors.initials: D
authors.lastname: Pressley
authors.forename: V
authors.initials: V
authors.lastname: Mazzaferro
authors.forename: C O
authors.initials: CO
authors.lastname: Esquivel
authors.forename: S
authors.initials: S
authors.lastname: Todo
authors.forename: B
authors.initials: B
authors.lastname: Banner
mesh_terms: D000527:Alprostadil / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001706:Biopsy; D004285:Dogs; D011464:Epoprostenol / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D006085:Graft Survival / Q000187:drug effects*; D007249:Inflammation / Q000503:physiopathology; D007668:Kidney / Q000473:pathology; D016030:Kidney Transplantation; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D010976:Platelet Count; D011806:Quinolinium Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D012079:Renal Circulation; D013552:Swine; D014183:Transplantation, Heterologous
chemical_list: D010972:Platelet Activating Factor; D011806:Quinolinium Compounds; C050531:SRI 63-441; D011464:Epoprostenol; D000527:Alprostadil