The investigator has shown that IL-1B causes a dramatic and prolonged induction of iNOS in rat aortic smooth muscle cells (RASMC) in culture, and that transforming growth factor (TGF-B1), but not dexamethasone, inhibits iNOS gene transcription after its IL-1B mediated induction. The investigator hypothesizes that TGF-B1 may prevent hypotension in animals in septic shock. This study is to investigate molecular mechanisms of TGF-B1 induced down regulation of the iNOS gene in RASMC in vitro, and to test the effect of TGF-B1 in preventing hypotension in septic shock in vivo. The investigator will first characterize the specific nucleotide sequences required for induction of the iNOS gene by IL-1B. Using these nucleotide sequences, the investigator will proceed to isolate the genes coding for the nuclear proteins that bind to the nucleotide sequence (cis acting elements), and then study the expression patterns and structure- function relationships in these genes. The investigator will then go on to study the down regulation of IL-1B induced iNOS gene transcription by TGF-B1. TGF-B1 could down regulate iNOS gene transcription via IL-1B responsive elements or via an IL-1B independent silencer. Finally, studies will test whether TGF-B1 will inhibit the induction of iNOS gene expression and hypotension in rats with septic shock.
NIH ExPorter
NIH ExPorter