This Article Full Text (PDF) References Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Gilad, E. Articles by Szabo, C. Search for Related Content PubMed Articles by Gilad, E. Articles by Szabo, C. Social Bookmarking                         What's this?

Effects of radiodetoxified endotoxin on nitric oxide production in J774 macrophages and in endotoxin shock

Division of Critical Care Medicine, Children's Hospital Medical Center, Cincinnati, Ohio, USA

B. Zingarelli

Division of Critical Care Medicine, Children's Hospital Medical Center, Cincinnati, Ohio, USA

M. O'Connor

Division of Critical Care Medicine, Children's Hospital Medical Center, Cincinnati, Ohio, USA

A.L. Salzman

Division of Critical Care Medicine, Children's Hospital Medical Center, Cincinnati, Ohio, USA

L. Bertok

The Frédéric Joliot-Curie National Research Institute for Radiobiology and Radiohygiene, Budapest, Hungary

C. Szabo

Division of Critical Care Medicine, Children's Hospital Medical Center, Cincinnati, Ohio, USA

Radiodetoxified lipopolysaccharide (RD-LPS) is a ⁶⁰Co-gamma-irradiated LPS with a modified structure, which decreases its toxic effects. To obtain a better understanding of the mechanism of the reduced toxicity of RD-LPS, here we studied the effect of RD-LPS on the regulation of nitric oxide (NO) production in vitro and in vivo. In control cells, stimulation by native LPS (10 µg/ml) induced the expression of the inducible NO synthase (iNOS) and production of NO, as measured by increase in the concentration of nitrite, breakdown product of NO. Pre-exposure of the cells for 24 h to a subthreshold concentration of RD-LPS (10 ng/ml) induced a complete desensitization to the LPS-induced NO production in comparison to control cells (P < 0.01). On the contrary, pre-exposure of the cells with native LPS (10 ng/ml) did not reduce LPS-induced NO synthesis. RD-LPS induced a smaller production of tumor necrosis factor (TNF) than native LPS, but did not induce a desensitization against subsequent LPS-induced TNF synthesis. ln in vivo studies, pretreatment of rats with repeated doses of sublethal RD-LPS (1 mg/kg/day i.p. for 4 days) inhibited increase of plasma nitrate/nitrite levels, NO production in peritoneal macrophages ex vivo and induction of lung iNOS activity, in response to a high-dose LPS challenge (15 mg/kg i.p.) given at the fifth day. Pretreatment with repeated sublethal doses of the native LPS (1 mg/kg/day i.p.) did not affect NO production in rats subjected to endotoxic shock. The results demonstrate that RD-LPS induces tolerance to the stimulatory effect of LPS on NO synthesis. Suppression of iNOS induction was only observed with RD-LPS, but not with native LPS in the models used herein. It remains to be further investigated whether suppression of iNOS induction by RD-LPS contributes to the protective effects of this compound in shock and inflammation.

Journal of Endotoxin Research, Vol. 3, No. 6, 513-519 (1996)
DOI: 10.1177/096805199600300610


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?