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From the Department of Nephrology,*
University of Essen,
Essen, Germany; and the Semmelweis
Medical University,
Budapest, Hungary
In vivo administration of low doses of lipopolysaccharide (LPS) to
rodents can protect these animals from subsequently
administrated, usually lethal doses of endotoxin or LPS.
In this study we tested the effects of LPS pretreatment 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 kidney were clamped for 30 or 45 minutes on day 0.
Creatinine levels and survival of animals were monitored. To test the
involvement of cytokines, additional animals were harvested
before ("time 0") and 15 minutes, 1,
2, 8, and 16 hours after reperfusion for
histology, immunohistochemistry, terminal
deoxynucleotidyltransferase-mediated UTP end-labeling assay,
and reverse transcriptase-polymerase chain reaction analysis (including
tumor necrosis factor (TNF)-
, interleukin (IL)-1,
IL-6, inducible nitric oxide synthase (iNOS),
and interferon (IFN)-
messenger RNA (mRNA)). In controls,
renal ischemia of 30 minutes was nonlethal, whereas 73% of the
animals died within 48 ± 18 hours, after 45 minutes of
ischemia. All different doses of LPS protected the animals from lethal
renal ischemia/reperfusion injury. Starting at similar levels,
serum creatinine increased significantly in controls but not in
LPS-pretreated animals over time. As early as 2 hours after
reperfusion, tubular cell damage was significantly more
pronounced in controls 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 leukocytic
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 revealed
significantly more apoptotic cells in controls compared with
LPS-pretreated animals. IL-1, IFN-, and iNOS
mRNA expression did not differ between the groups throughout the time
points examined. However, the expression of TNF- mRNA was
significantly increased at 2 hours and IL-6 mRNA was significantly
down-regulated before ischemia and shortly after reperfusion in the
LPS-pretreated kidneys. Therefore, we found that sublethal
doses of LPS induced cross-tolerance to renal ischemia/reperfusion
injury. Our data suggest that increased TNF- and reduced IL-6 mRNA
expression might be responsible. However, more studies are
needed to decipher the exact mechanism.
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