# 2267 Hepatic Protection in E. Coli Septic Shock as Well as Hemorrhagic
Shock by MMPI Inhibition.
Alberto S. Santibanez-Gallerani, Annabelle Barber, George Thomas
Shires, Shelly J. Williams, Peter J. Mazolewski, Jeff Avansino, Brett
Murray, Shawn Davis, Yan Zhao, Las Vegas, NV
Cytokines such as TNF-a and IL-6 are elevated in hemorrhagic shock.
Experimental models of septic shock have produced controversial results
and a lack of clinical correlation. Recently, Matrix Metalloproteinase Inhibitors
(MMPI) have been observed to decrease TNF-a via inhibition of
TNF-a convertase. MMPI has recently been shown to offer hepatic protection
in hemorrhagic shock. The purpose of this study was to investigate
the effects of MMPI in vivo on the levels of TNF-a and IL-6 when
exposed to Escherichia coli induced septic shock as compared to hemorrhagic
shock (HS) produced by 35% blood volume reduction. Sprague-
Dawley rats (n=24)(300-400 grams) were divided into: HS, E. coli sepsis
(ATCC 25922, 4.5 x 107 CFU), and with and without the administration
of MMPI (2.5 µg/kg British Biotech 1101). MMPI was administered 15
minutes post shock. Hepatic membrane potentials (Em) and hepatic blood
flows were measured at baseline, at 90, and 180 minutes. Carotid arterial
blood samples were analyzed for IL-6 and TNF-a. Student T-test statistical
analysis was performed. It is concluded that MMPI has a protective effect
on hepatic integrity as demonstrated by a stabilization of the membrane
potential in both forms of shock. This stabilization is independent of the
mean arterial pressure and hepatic blood flow and is most likely the result
of the inhibition of the TNF-a cascade. Interestingly, IL-6 levels were
influenced differently depending on the type of shock; thus, suggesting
two independent pathways of induction, and possibly accounting for the
differences in clinical correlation.
|