Lipopolysaccharide pretreatment protects from renal ischemia/reperfusion injury - Possible connection to an interleukin-6-dependent Pathway

In vivo administration of low doses of lipopolysaccharide (LPS) to rodents can protect these animals from subsequently administrated, usually lethal d oses of endotoxin or LPS. In this study we tested the effects of LPS pretre atment on ischemia/reperfusion injury in the kidney. Male C57/B1 mice were pretreated with different doses of LPS or phosphate-buffered saline on days -4 and -3. The right kidney was removed, and the vessels of the left kidne y were clamped for 30 or 45 minutes on day 0. Creatinine levels and surviva l of animals were monitored. To test the involvement of cytokines, addition al animals were harvested before ("time 0") and 15 minutes, 1, 2, 8, and 16 hours after reperfusion for histology, immunohistochemistry, terminal deox ynucleotidyl-transferase-mediated UTP end-labeling assay, and reverse trans criptase-polymerase chain reaction analysis (including tumor necrosis facto r (TNF)-alpha, interleukin. (IL)-1, IL-6, inducible nitric oxide synthase ( iNOS), and interferon (IFN)-gamma messenger RNA (mRNA)). In controls, renal ischemia of 30 minutes was nonlethal, whereas 73% of the animals died with in 48 +/- 18 hours, after 45 minutes of ischemia. All different doses of LP S protected the animals from lethal renal ischemia/reperfusion injury. Star ting at similar levels, serum creatinine increased significantly in control s but not in LPS-pretreated animals over time. As early as 2 hours after re perfusion, tubular cell damage was significantly more pronounced in control s than in LPS-treated mice. In controls, tubules deteriorated progressively until 8 hours of reperfusion. At this time, more than 50% of tubular cells were destroyed. This destruction was accompanied by a pronounced leukocyti c infiltration, predominantly by macrophages. In contrast, LPS pretreatment prevented the destruction of kidney tissue and infiltration by leukocytes. The terminal deoxynucleotidyltransferase-mediated UTP end-labeling assay r evealed significantly more apoptotic cells in controls compared with LPS-pr etreated animals. IL-1, IFN-gamma, and iNOS mRNA expression did not differ between the groups throughout the time points examined. However, the expres sion of TNF-alpha mRNA was significantly increased at 2 hours and IL-6 mRNA was significantly down-regulated before ischemia and shortly after reperfu sion in the LPS-pretreated kidneys. Therefore, me found that sublethal dose s of LPS induced cross-tolerance to renal ischemia/reperfusion injury. Om d ata suggest that increased TNF-alpha and reduced IL-6 mRNA expression might be responsible. However, more studies are needed to decipher the exact mec hanism.