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Direct Evidence That Induced Nitric Oxide Production in Hepatocytes Prevents Liver Damage During Lipopolysaccharide Tolerance in Rats

Direct Evidence That Induced Nitric Oxide Production in Hepatocytes Prevents Liver Damage During Lipopolysaccharide Tolerance in Rats

Yoshiaki Ebisawa, Toru Kono, Masashi Yoneda, Toshiyuki Asama, Naoyuki Chisato, Mutsubu Sugawara, Kazushi Ishikawa, Jun Iwamoto, Tokiyoshi Ayabe, Yutaka Kohgo, Shinichi Kasai

J Surg Res. 2004 May 15;118(2):183-9.

PMID: 15100007

Abstract:

Background:
The role of nitric oxide (NO) in lipopolysaccharide (LPS) tolerance in the liver has been investigated in a number of previous studies, but it is still not clear whether NO is cytotoxic or cytoprotective. The aims of this study were to investigate whether low-dose LPS (LLPS)-induced hepatic production of NO is beneficial and to clarify the origins of cytoprotective NO-producing cells in the liver during LPS tolerance.
Materials and methods:
Male Wistar rats received saline or LLPS intraperitoneally (i.p.; 0.01-1000 microg/kg) followed by a high dose of LPS (HLPS, 5 mg/kg) at various time intervals (4-16 h). NG-nitro-L-arginine methyl ester (L-NAME) was used to investigate the effects of inhibition of NOS. 4,5-Diaminofluorescein (DAF-2) was used to identify NO-producing cells in isolated liver cells in vitro. At various time points (4-16 h) after saline or LLPS (1 microg/kg, i.p.) injection, hepatocytes and Kupffer cells were isolated, incubated in 7 microm DAF-2 diacetate, and perfused with Krebs solution. Illumination at 495 nm revealed DAF-fluorescence (515 nm) in isolated cells under confocal laser fluorescence microscopy. The NO production in hepatocytes and Kupffer cells was assessed by the number of labeled cells per 1000 cells or per 100 cells, respectively.
Results:
Pretreatment with LLPS (0.1-100 microg/kg) resulted in a significant reduction (maximal at 8 h) of the HLPS-induced liver damage. L-NAME abolished the LLPS-induced protection. The NO production in hepatocytes was significantly increased and reached a maximum of 84% of all cells 8 h after LLPS administration. By contrast, the NO production in Kupffer cells remained constant at 95%, even following preinjection of LLPS.
Conclusion:
LLPS-induced NO in hepatocytes, but not in Kupffer cells, exhibits cytoprotective effects on HLPS-induced liver damage, suggesting that NO has a beneficial role in the induction of the early phase of LPS tolerance.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4241315	4,5-Diaminofluorescein diacetate solution			Price

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