Tacrolimus suppresses tumour necrosis factor-alpha and protects against splanchnic artery occlusion shock

1 Tumour necrosis factor (TNF-alpha) is a pleiotropic cytokine which is dee ply involved in the pathogenesis of splanchnic artery occlusion (SAO) shock . Tacrolimus, formerly known as FK506, is a macrolide antibiotic. that bloc ks the transcription of several proinflammatory cytokines including TNF-alp ha. 2 Male anaesthetized rats were subjected to clamping of the splanchnic arte ries for 45 min. This surgical procedure resulted in an irreversible state of shock (SAO shock). Sham operated animals were used as controls. SAO shoc ked rats had a decreased survival rate (0% at 4 h of reperfusion, while sha m shocked rats survived more than 4 h), enhanced serum TNF-alpha concentrat ions (415+/-12 U ml(-1)), decreased mean arterial blood pressure (MAP), leu kopenia and increased ileal leukocyte accumulation studied by means of myel operoxidase activity (MPO=7.5 +/- 0.3 U g(-1) tissue). Moreover aortic ring s from shocked rats showed a marked hyporeactivity to phenylephrine (PE, 1 nM-10 mu M), reduced responsiveness to acetylcholine (ACh, 10 nM - 10 mu M) and increased staining for intercellular adhesion molecule-1 (ICAM-1). Fur thermore increased mRNA for TNF-alpha was observed in peritoneal macrophage s of SAO shocked rats. 3 Tacrolimus (100 mu g kg(-1), 5 min after splanchnic arteries occlusion) i ncreased survival rate (SAO + Tacrolimus = 100% at 4 h of reperfusion), rev erted the marked hypotension, reduced serum TNF-alpha (15 +/- 3 U ml(-1)), ameliorated leukopenia. reduced ileal MPO (0.9 +/- 0.01 U g(-1) tissue), re stored to control values the hyporeactivity, to PE, improved the reduced re sponsiveness to ACh and blunted the enhanced immunostaining for ICAM-1 in t he aorta. Finally tacrolimus suppressed cytokine mRNA levels in peritoneal macrophages. 4 The data suggest that tacrolimus may represent a new therapeutic approach in circulatory shock.