BACKGROUND: The spin trap alpha-phenyl-N-tert-butyl-nitrone (PBN) affords protection from the lethality of septic (lipopolysaccharide) shock. We hypothesized that PBN may work through down-regulation of the sepsis-induced cytokine cascade. METHODS: C3H/HEN mice received 30 mg/kg lipopolysaccharide 15 minutes after pretreatment with PBN or vehicle. Animals were monitored for differences in behavior, histopathologic studies, survival, and serum levels of tumor necrosis factor (TNF-alpha), interferon-gamma (IFN-gamma), and interleukin-6 (IL-6) after lipopolysaccharide. Northern blot analyses of TNF, IFN-gamma, c-fos, and IL-6 transcripts were also performed. RESULTS: Seventy-two-hour survival was significantly higher in the PBN-treated (59/60) compared with the saline-treated animals (13/60; p2 less than 0.005), and the PBN group exhibited a blunted endotoxemic response. TNF levels were significantly lower in the PBN-treated animals at 1 to 6 hours, whereas IFN-gamma levels were depressed at 8 hours. PBN down-regulated TNF transcription at 30 minutes, with maximum lowering of all cytokine transcripts at 6 hours. PBN depressed c-fos transcription within 15 minutes of lipopolysaccharide injection. CONCLUSIONS: Spin trap protection from endotoxemia may be related to interruption of the cytokine network, with profound effects on transcription and protein elaboration. Such compounds may prove useful in not only sepsis but also other cytokine-free radical-related pathophysiologic alterations.
BACKGROUND: The spin trap alpha-phenyl-N-tert-butyl-nitrone (PBN) affords protection from the lethality of septic (lipopolysaccharide) shock. We hypothesized that PBN may work through down-regulation of the sepsis-induced cytokine cascade. METHODS: C3H/HEN mice received 30 mg/kg lipopolysaccharide 15 minutes after pretreatment with PBN or vehicle. Animals were monitored for differences in behavior, histopathologic studies, survival, and serum levels of tumor necrosis factor (TNF-alpha), interferon-gamma (IFN-gamma), and interleukin-6 (IL-6) after lipopolysaccharide. Northern blot analyses of TNF, IFN-gamma, c-fos, and IL-6 transcripts were also performed. RESULTS: Seventy-two-hour survival was significantly higher in the PBN-treated (59/60) compared with the saline-treated animals (13/60; p2 less than 0.005), and the PBN group exhibited a blunted endotoxemic response. TNF levels were significantly lower in the PBN-treated animals at 1 to 6 hours, whereas IFN-gamma levels were depressed at 8 hours. PBN down-regulated TNF transcription at 30 minutes, with maximum lowering of all cytokine transcripts at 6 hours. PBN depressed c-fos transcription within 15 minutes of lipopolysaccharide injection. CONCLUSIONS:Spin trap protection from endotoxemia may be related to interruption of the cytokine network, with profound effects on transcription and protein elaboration. Such compounds may prove useful in not only sepsis but also other cytokine-free radical-related pathophysiologic alterations.
Authors: Robert A Floyd; Richard D Kopke; Chul-Hee Choi; Steven B Foster; Sabrina Doblas; Rheal A Towner Journal: Free Radic Biol Med Date: 2008-08-29 Impact factor: 7.376
Authors: Robert A Floyd; Hugo C Castro Faria Neto; Guy A Zimmerman; Kenneth Hensley; Rheal A Towner Journal: Free Radic Biol Med Date: 2013-02-16 Impact factor: 7.376
Authors: Patricia Coutinho de Souza; Nataliya Smith; Oluwatomisin Atolagbe; Jadith Ziegler; Charity Njoku; Megan Lerner; Marilyn Ehrenshaft; Ronald P Mason; Bill Meek; Scott M Plafker; Debra Saunders; Nadezda Mamedova; Rheal A Towner Journal: Free Radic Biol Med Date: 2015-06-26 Impact factor: 7.376
Authors: Patricia Coutinho de Souza; Nataliya Smith; Richard Pody; Ting He; Charity Njoku; Robert Silasi-Mansat; Florea Lupu; Bill Meek; Hong Chen; Yunzhou Dong; Debra Saunders; Albert Orock; Erik Hodges; Sarah Colijn; Nadezda Mamedova; Rheal A Towner Journal: Am J Nucl Med Mol Imaging Date: 2015-06-15