부산대학교 도서관

Gentamicin is a mainstay in treating gram-negative sepsis. However, it also may potentiate endotoxin (LPS)-driven plasma TNF-[alpha] increases. Because gentamicin accumulates in renal tubules, this study addressed whether gentamicin directly alters LPS-driven tubular cell TNF-[alpha] production. HK-2 proximal tubular cells were incubated for 18 h with gentamicin (10-2,000 [micro]g/ml). Subsequent LPS-mediated TNF-[alpha] increases (at 3 or 24 h; protein/mRNA) were determined. Gentamicin effects on overall protein synthesis ([[sup.35]S]methionine incorporation), monocyte chemoattractant protein-1 (MCP-1) levels, and LPS-stimulated TNF-[alpha] generation by isolated mouse proximal tubules also were assessed. Finally, because gentamicin undergoes partial biliary excretion, its potential influence on gut TNF-[alpha]/MCP-1 mRNAs was probed. Gentamicin caused striking, dose-dependent inhibition of LPS-driven TNF-[alpha] production (up to 80% in HK-2 cells/isolated tubules). Surprisingly, this occurred despite increased TNF-[alpha] mRNA accumulation. Comparable changes in MCP-I were observed. These changes were observed at clinically relevant gentamicin concentrations and despite essentially normal overall protein synthetic rates. Streptomycin also suppressed LPS-driven TNF-[alpha] increases, suggesting an aminoglycoside drug class effect. Gentamicin doubled basal TNF-[alpha] mRNA in cecum and in small intestine after LPS. Gentamicin can suppress LPS-driven TNF-[alpha] production in proximal tubule cells, likely by inhibiting its translation. Overall preservation of protein synthesis and comparable MCP-1 suppression suggest a semiselective blockade within the LPS inflammatory mediator cascade. These results, coupled with increases in gut TNF-[alpha]/ MCP-1 mRNAs, imply that gentamicin may exert protean, countervailing actions on systemic cytokine/chemokine production during gram-negative sepsis. HK-2 cells; aminoglycosides; acute renal failure; tumor necrosis factor-[alpha]