Scavenging nitric oxide reduces hepatocellular injury after endotoxin challenge.
Sustained upregulation of inducible nitric oxide (NO) synthase in the liver after endotoxin [lipopolysaccharide (LPS)] challenge may result in hepatocellular injury. We hypothesized that administration of a NO scavenger, NOX, may attenuate LPS-induced hepatocellular injury. Sprague-Dawley rats received NOX or saline via subcutaneous osmotic pumps, followed 18 h later by LPS challenge. Hepatocellular injury was assessed using biochemical assays, light, and transmission electron microscopy (TEM). Interleukin (IL)-6 mRNA was measured by RT-PCR. Tumor necrosis factor (TNF)-alpha protein expression was determined by immunohistochemistry. NOX significantly reduced serum levels of ornithine carbamoyltransferase and aspartate aminotransferase. TNF-alpha and IL-6 expression were increased in the livers of saline-treated but not NOX-treated rats. Although there was no difference between groups by light microscopy, TEM revealed obliteration of the space of Disse in saline-treated but not in NOX-treated animals. Electron paramagnetic resonance showed the characteristic mononitrosyl complex in NOX-treated rats. We conclude that NOX reduces hepatocellular injury after endotoxemia. NOX may be useful in the management of hepatic dysfunction secondary to sepsis or other diseases associated with excessive NO production.
Nadler
E P
EP
Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh 15213, USA.
Dickinson
E C
EC
Beer-Stolz
D
D
Alber
S M
SM
Watkins
S C
SC
Pratt
D W
DW
Ford
H R
HR
D000818:Animals; D004578:Electron Spin Resonance Spectroscopy; D019446:Endotoxemia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D016166:Free Radical Scavengers / Q000494:pharmacology*; D015870:Gene Expression / Q000502:physiology; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D015850:Interleukin-6 / Q000235:genetics; D007728:Kupffer Cells / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008854:Microscopy, Electron; D009504:Neutrophils / Q000276:immunology; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013012:Sorbitol / Q000031:analogs & derivatives; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D016166:Free Radical Scavengers; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C404528:nitric oxide scavenger 100; D009569:Nitric Oxide; D013012:Sorbitol; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat