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Abstract

The changes in NO production induced by endotoxin (LPS) tolerance are controversial. The aim of this study was to explore modulation of NO production by LPS tolerance in different liver cell types and alveolar macrophages. Such cells were studied in three groups of male Sprague Dawley rats: non-tolerant rats (sal-LPS) received saline or no treatment 48 h before a 3 mg/kg LPS injection, tolerant rats received low dose LPS (0.5 mg/kg) 48 h before a second injection of saline (LPS-sal) or LPS 3 mg/kg (LPS-LPS). All injections were delivered i.v. Animals were studied 1 and 6 h after the second injection. NO production (assessed by nitrite release) by hepatocytes, Kupffer cells, endothelial cells and alveolar macrophages was simultaneously determined after 20 h of culture in the presence or in the absence of LPS, interferon-y (IFN) or both. Basal NO production by hepatocytes of tolerant and nontolerant LPS injected rats was high 1 h after the second injection, and was dramatically reduced 6 h after the second injection. Hepatocytes of tolerized LPSinjected (LPS-LPS) rats were significantly less sensitive to in vitro stimulation by LPS and IFN at 1 h than hepatocytes of tolerized saline-injected rats and this difference disappeared by 6 h. In Kupffer cells of tolerant rats 6 h after the second LPS injection, basal NO generation was significantly less than in nontolerant rats. In both cell types of tolerant LPS-LPS rats, in vitro stimulated NO production was moderately upregulated at 1 h and then highly upregulated at 6 h, whereas in nontolerant (sal-LPS) animals, stimulated NO production was only slightly upregulated or not at all. Sensitivity to LPS and IFN stimulation of Kupper cells of LPS-LPS rats was not different from Kupffer cells of LPS-sal rats at 1 h, but became significantly higher at 6 h relative to both LPS-sal and sal-LPS animals. In endothelial cells of tolerant saline-injected (LPS-sal) rats, basal NO production was significantly less than in the sal-LPS group both at 1 and 6 h after the second injection. In endothelial cells of tolerant LPS-LPS animals, a significant upregulation of stimulated NO production higher than in the other groups was observed only at 1 h. No difference was evident in basal or stimulated NO production by alveolar macrophages of the different treatment groups, except for a significant increase in basal NO production in tolerant rats (LPS-LPS) at 6 h relative to 1 h after the second LPS injection.

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Effect of acute endotoxin tolerance on NO production by isolated hepatic parenchymal and nonparenchymal cells and alveolar macrophages in rats

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