Hepatic integrity dependent on matrix metalloproteinase inhibition, not tumor necrosis factor alpha or different bleeding rates

Discrepancies in the levels of proinflammatory cytokines such as tumor necr osis factor alpha (TNF-alpha) following hemorrhagic shock (HS) may be due t o the inconsistent rates of bleeding. The purpose of this study was to inve stigate the effects of rapid versus slow bleeding rates on TNF-alpha levels and if inhibition of TNF-alpha convertase by a matrix metalloproteinase in hibitor (MMPI) affects hepatic integrity in animals exposed to 35% HS. Spra gue-Dawley male rats (n = 24, 300-350 g) were divided into four groups: HS 15 (produced over 15 min), HS 30 (produced over 30 min), and HS with MMPI ( 2.5 mg/kg British Biotech 1101: HS15 + MMPI, HS30 + MMPI). Mean arterial bl ood pressure (MAP), serum TNF-alpha, levels, and hepatic resting membrane p otentials (E-m) were obtained. A Student t test was performed. TNF-alpha le vels for HS 15, HS15 + MMPI, HS 30, and HS 30 + MMPI were 474, 40, 32, and 50 pg/ml, respectively. The hepatic resting membrane potentials for HS 15, HS15 + MMPI, HS 30, and HS 30 + MMPI were -26, -30, -23, and -31 mV,respect ively. In conclusion, circulating TNF-alpha levels are affected by the rate of bleeding in hemorrhagic shock. However, despite the differences in the magnitude of TNF-alpha in untreated animals, hepatic integrity was compromi sed. Interestingly, MMPI, an inhibitor of TNF-alpha convertase, stabilizes the membrane potential in both types of hemorrhagic shock. (C) 2000 Academi c Press.