"Subclinical" gentamicin nephrotoxicity: a potential risk factor for exaggerated endotoxin-driven TNF-alpha production.
This study sought to determine whether gentamicin, a mainstay in treating Gram-negative sepsis, alters endotoxin (lipopolysaccharide; LPS)-driven TNF-alpha increases. CD-1 mice received 1 day of gentamicin treatment. Either 0, 24, or 72 h later, gentamicin-treated and control mice were injected with LPS. Renal cortical and plasma TNF-alpha, as well as MCP-1, protein levels were measured 2 or 24 h post-LPS injection. Renal cortical mRNAs for TNF-alpha, MCP-1, IL-10, and inducible nitric oxide synthase (iNOS) were also determined. Finally, gentamicin's potential impact(s) on TNF-alpha/MCP-1 mRNA levels in nontraditional "target" organs (liver, spleen) was assessed. Gentamicin, when administered alone, slightly increased renal cortical TNF-alpha and MCP-1 mRNAs, but without changing plasma or renal TNF-alpha/MCP-1 protein levels. The gentamicin protocol induced no overt renal damage (assessed by blood urea nitrogen, creatinine, and histology). Nevertheless, gentamicin augmented LPS responsiveness, as manifested, in part, by a doubling of LPS-induced plasma TNF-alpha increases (vs. LPS injection alone). Plasma and renal cortical MCP-1 protein levels were also selectively enhanced. Gentamicin augmented LPS-driven renal mRNA increases (TNF-alpha, MCP-1, IL-10, iNOS). However, this was not an entirely renal-specific response, since gentamicin also enhanced basal and LPS-stimulated hepatic TNF-alpha mRNA levels. Subclinical gentamicin toxicity can potentiate LPS-driven TNF-alpha increases. Alterations in multiple proinflammatory (TNF-alpha; MCP-1; iNOS) and anti-inflammatory (IL-10) genes in the kidney, and possibly in extrarenal organs, may be involved. Thus gentamicin's activity in Gram-negative sepsis may extend beyond its traditional antimicrobial effect.
Zager
Richard A
RA
Department of Medicine, University of Washington, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Rm. D2-190, Seattle, WA 98109, USA. dzager@fhcrc.org
D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D004731:Endotoxins / Q000633:toxicity*; D005839:Gentamicins / Q000633:toxicity*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000096:biosynthesis / Q000235:genetics; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013154:Spleen / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000900:Anti-Bacterial Agents; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D004731:Endotoxins; D005839:Gentamicins; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases