Jessica Feinleib, MD

Cardiac Fellow , Dept. of Anesthesiology and Cardiology

In many cases in clinical medicine, the advent of an inflammatory insult such as infection, trauma, severe burn or hemorrhage cannot be anticipated.  Hence, the ability of a drug to treat inflammation and its sequelae, when delivered after an inflammatory insult, has high clinical relevance.  The majority of the devastating effects of inflammation are mediated through tumor necrosis factor alpha (TNF-?).  HMG-CoA Reductase Inhibitors (Statins) have been shown to have the inverse effects on endothelial cell function compared to those of TNF-?. The potential ability of statins to rescue endothelial cell gene expression from TNF-? induced changes by has not been demonstrated.  Additionally, whether statins can abrogate or rescue changes in endothelial permselectivity that are induced by TNF-? also remains to be examined.  Our hypothesis is that statin treatment can either fully or partially repair the effects of inflammatory mediators on endothelial cells.  Testing this hypothesis will help to provide an intellectual basis for the appropriateness of statin therapy following inflammatory insult.  To date there has been no comprehensive evaluation of the effects of statins on endothelial cells after TNF-? stimulation in vitro or in vivo.

Specifically, we will test whether statins can and re-establish endothelial cell permselectivity through expression of the tight-junction protein occludin, preserve expression of anti-coagulant factor thrombomodulin (TM), and reduce endothelial cell expression of the pro-coagulant tissue factor (TF), as well as induce re-expression of endothelial nitric oxide synthase (eNOS).  We hypothesize that the cell signal transduction pathway by which statins accomplish these effects include the Toll-like receptor 2 and 4, the transcription factors nuclear factor kappa B (NF?B), MADS-box family of transcription factors 2A (MEF2A) and Krüppel-like family 2 (KLF2), and the GTPase Rho and the kinase Rho-binding kinase (ROCK).