The cytokine-adhesion molecule cascade in ischemia/reperfusion injury of the rat kidney. Inhibition by a soluble P-selectin ligand.

Abstract

Ischemia/reperfusion (I/R) injury associated with renal transplantation may influence both early graft function and late changes.The initial ( Յ 7 d) events of warm and in situ perfused cold ischemia of native kidneys in uninephrectomized rats were examined.mRNA expression of the early adhesion molecule, E-selectin, peaked within 6 h; PMNs infiltrated in parallel.T cells and macrophages entered the injured kidney by 2-5 d; the associated upregulation of MHC class II antigen expression suggested increased immunogenicity of the organ.Th1 products (IL-2, TNF ␣ , IFN ␥ ) and macrophage-associated products (IL-1, IL-6, TGF ␤ ) remained highly expressed after 2 d.To examine directly the effects of selectins in I/R injury, a soluble P-selectin glycoprotein ligand (sPSGL) was used.Ischemic kidneys were perfused in situ with 5 g of sPSGL in UW solution; 50 g was administered intravenously 3 h after reperfusion.E-selectin mRNA remained at baseline, leukocytes did not infiltrate the injured organs throughout the 7-d period, and their associated products were markedly inhibited.Class II expression did not increase.No renal dysfunction secondary to I/R occurred.The early changes of I/R injury may be prevented by treatment with soluble P-and E-selectin ligand.This may reduce subsequent host inflammatory responses after transplantation.( J. Clin.Invest.1997.99:2682-2690.)Key words: P-selectin • E-selectin • cytokine • adhesion molecule • P-selectin glycoprotein ligand Methods Animals.Inbred male Lewis (LEW) rats (Harlan Sprague-Dawley, Indianapolis, IN) of 250-300 g were used throughout the experiments. Experimental design and operative technique.Three experimental models were examined.The initial events developing after cold I/R were examined in detail with particular reference to inflammatory molecules, cellular infiltration, and expression of associated products.Patterns occurring after warm ischemia were used for comparison.