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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

3H-1,2-Dithiole-3-thione Targets Nuclear Factor B to Block Expression of Inducible Nitric-Oxide Synthase, Prevents Hypotension, and Improves Survival in Endotoxemic Rats

W. Harry Feinstone Center for Genomic Research, University of Memphis, Memphis, Tennessee (A.R.K., Y.H., S.B., C.H.S., T.R.S.); Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire (B.D.R.); and Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (T.W.K.)

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) B, mechanistic studies show that D3T blocks NFB nuclear translocation and DNA binding and that these effects are accompanied by changes in the levels of phospho-inhibitor of NFB. 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 NFB and iNOS pathways.

Address correspondence to: Thomas R. Sutter, W. Harry Feinstone Center for Genomic Research, 201 Life Science Building, University of Memphis, Memphis, TN 38152. E-mail: tsutter{at}memphis.edu