The involvement of tumour necrosis factor-alpha in the protective effects of 17 beta oestradiol in splanchnic ischaemia-reperfusion injury.

Abstract

1. Tumour necrosis factor-alpha (TNF-alpha) is a cytokine that is implicated in the pathogenesis of ischaemic states and atherosclerosis. We tested the hypothesis that the vasoprotective effects of the oestrogens may be mediated in vivo by inhibition of the formation of TNF-alpha. 2. Anaesthetized rats, subjected to total occlusion of the superior mesenteric artery and the coeliac trunk for 45 min developed a severe shock state resulting in a fatal outcome within 75-90 min after the release of occlusion. Sham-operated animals were used as controls. 3. Splanchnic artery occlusion (SAO) shocked rats had a marked hypotension, enhanced levels of TNF-alpha in serum and macrophages, leukopenia and increased ileal leukocyte accumulation, studied by means of myeloperoxidase activity (MPO). Furthermore, aortae from SAO rats showed a marked hyporeactivity to phenylephrine (PE, 1 nM-10 microM), reduced responsiveness to acetylcholine (ACh, 10 nM-10 microM) and an increased staining for intercellular adhesion molecule-1 (ICAM-1). 4. In vivo administration of 17 beta oestradiol (500 micrograms kg-1, i.m., three hours before the induction of SAO) increased survival rate (100%, 4 h after SAO), enhanced mean arterial blood pressure; reduced serum TNF-alpha (25 +/- 5 u ml-1 vs 379 +/- 16 u ml-1), ameliorated leukopaenia and reduced ileal MPO (0.7 +/- 0.02 u 10(-3) g-1 tissue vs 4.2 +/- 0.4 u 10(-3) g-1 tissue). Furthermore aortae from SAO rats treated with 17 beta oestradiol exhibited a greater contractile response to phenylephrine, improved responsiveness to ACh and a blunted staining of ICAM-1. Finally 17 beta oestradiol, added in vitro to peritoneal macrophages collected from untreated SAO rats, significantly reduced TNF-alpha production. 5. Our results suggest that inhibition of TNF-alpha in vivo may explain, at least in part, the vasoprotective effects of oestrogens.