TY - JOUR
T1 - 3H-1,2-dithiole-3-thione targets nuclear factor κB to block expression of inducible nitric-oxide synthase, prevents hypotension, and improves survival in endotoxemic rats
AU - Karuri, Asok R.
AU - Huang, Yong
AU - Bodreddigari, Sridevi
AU - Sutter, Carrie Hayes
AU - Roebuck, Bill D.
AU - Kensler, Thomas W.
AU - Sutter, Thomas R.
PY - 2006/4
Y1 - 2006/4
N2 - Septicemia is a major cause of death associated with noncoronary intensive care. Systemic production of nitric oxide (NO) by inducible nitric-oxide synthase (iNOS) is a major cause of hypotension and poor organ perfusion seen in septic shock. Here, we show that pretreatment of F344 rats with the cancer chemoprotective agent 3H-1,2-dithiole-3-thione (D3T) blocks lipopolysaccharide (LPS)-mediated induction of hepatic iNOS and significantly reduces the associated serum levels of NO metabolites and enzyme markers of toxicity provoked by treatment with LPS. Immunohistochemical analysis shows that this protective effect is largely due to suppression of iNOS expression in hepatocytes. Importantly, pretreatment of animals with D3T blunts LPS-mediated hypotension and dramatically increases their survival. Inasmuch as iNOS expression can be regulated by nuclear factor (NF) κB, mechanistic studies show that D3T blocks NFκB nuclear translocation and DNA binding and that these effects are accompanied by changes in the levels of phospho-inhibitor of NFκB. In conclusion, this study identifies new drug classes and targets that may improve the prevention and treatment of septic shock, as well as chronic diseases associated with the NFκB and iNOS pathways.
AB - Septicemia is a major cause of death associated with noncoronary intensive care. Systemic production of nitric oxide (NO) by inducible nitric-oxide synthase (iNOS) is a major cause of hypotension and poor organ perfusion seen in septic shock. Here, we show that pretreatment of F344 rats with the cancer chemoprotective agent 3H-1,2-dithiole-3-thione (D3T) blocks lipopolysaccharide (LPS)-mediated induction of hepatic iNOS and significantly reduces the associated serum levels of NO metabolites and enzyme markers of toxicity provoked by treatment with LPS. Immunohistochemical analysis shows that this protective effect is largely due to suppression of iNOS expression in hepatocytes. Importantly, pretreatment of animals with D3T blunts LPS-mediated hypotension and dramatically increases their survival. Inasmuch as iNOS expression can be regulated by nuclear factor (NF) κB, mechanistic studies show that D3T blocks NFκB nuclear translocation and DNA binding and that these effects are accompanied by changes in the levels of phospho-inhibitor of NFκB. In conclusion, this study identifies new drug classes and targets that may improve the prevention and treatment of septic shock, as well as chronic diseases associated with the NFκB and iNOS pathways.
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U2 - 10.1124/jpet.105.096396
DO - 10.1124/jpet.105.096396
M3 - Article
C2 - 16371450
AN - SCOPUS:33645118005
SN - 0022-3565
VL - 317
SP - 61
EP - 67
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 1
ER -