Acute nephrotoxic and obstructive injury primes the kidney to endotoxin-driven cytokine/chemokine production.

Gram-negative sepsis is a frequent complication in patients with acute renal failure. This study tested whether acute tubular injury, for example, induced by cisplatin (CP) or urinary tract obstruction, enhances renal cytokine responses to endotoxin (lipopolysaccharide (LPS)), potentially contributing to tissue damage. CD-1 mice were subjected to CP or vehicle injection. After 24 or 72 h, LPS or its vehicle was given. At 2 h post LPS or vehicle administration, plasma/renal cortical tumor necrosis factor (TNF)-alpha, monocyte chemoattractant protein-1 (MCP-1), and interleukin-10, and their corresponding renal cortical mRNAs were assessed (representing pro-anti-inflammatory cytokines, and a chemokine, respectively). Comparable studies were conducted in mice 24 h post unilateral ureteral obstruction (UUO). Cultured human proximal tubular (HK-2) cell TNF-alpha responses to CP+/-LPS were also assessed. CP alone caused either minimal or no increases in cytokine levels. However, CP dramatically augmented cytokine responses to LPS (up to 5-10 x vs LPS alone). The cytokine increases were paralleled by changes in their mRNAs. UUO also sensitized to LPS. CP alone did not alter HK-2 cell TNF-alpha/mRNA. However, CP 'primed' the cells to LPS (approximately 50-100% greater TNF-alpha/mRNA increases vs LPS alone). CP+LPS also caused synergistic cell death (lactate dehydrogenase release). We conclude that (1) diverse forms of tubular injury can sensitize the kidney to LPS, increasing cytokine production; (2) proximal tubules are involved; (3) LPS 'priming' has broad-based consequences, impacting diverse pro- and anti-inflammatory pathways; and (4) increased transcriptional events may be at least partially involved.

Parenteral iron compounds sensitize mice to injury-initiated TNF-alpha mRNA production and TNF-alpha release.

Intravenous Fe is widely used to treat anemia in renal disease patients. However, concerns of potential Fe toxicity exist. To more fully define its spectrum, this study tested Fe's impact on systemic inflammation following either endotoxemia or the induction of direct tissue damage (glycerol-mediated rhabdomyolysis). The inflammatory response was gauged by tissue TNF-alpha message expression and plasma TNF-alpha levels. CD-1 mice received either intravenous Fe sucrose, -gluconate, or -dextran (FeS, FeG, or FeD, respectively; 2 mg), followed by either endotoxin (LPS) or glycerol injection 0-48 h later. Plasma TNF-alpha was assessed by ELISA 2-3 h after the LPS or glycerol challenge. TNF-alpha mRNA expression (RT-PCR) was measured in the kidney, heart, liver, lung, and spleen with Fe +/- LPS treatment. Finally, the relative impacts of intramuscular vs. intravenous Fe and of glutathione (GSH) on Fe/LPS- induced TNF-alpha generation were assessed. Each Fe preparation significantly enhanced LPS- or muscle injury-mediated TNF-alpha generation. This effect was observed for at least 48 h post-Fe injection, a time at which plasma iron levels were increased by levels insufficient to fully saturate transferrin. Fe did not independently increase plasma TNF-alpha or tissue mRNA. However, it potentiated postinjury-induced TNF-alpha mRNA increments and did so in an organ-specific fashion (kidney, heart, and lung; but not in liver or spleen). Intramuscular administration, but not GSH treatment, negated Fe's ability to synergize LPS-mediated TNF-alpha release. We conclude 1) intravenous Fe can enhance TNF-alpha generation during LPS- or glycerol-induced tissue damage; 2) increased TNF-alpha gene transcription in the kidney, heart, and lung may contribute to this result; and 3) intramuscular administration, but not GSH, might potentially mitigate some of Fe's systemic toxic effects.