他克莫司可抑制肿瘤坏死因子-α，并预防内脏动脉闭塞性休克。

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

作者信息

Squadrito F, Altavilla D, Squadrito G, Ferlito M, Campo G M, Arlotta M, Grimaldi S, Quartarone C, Saitta A, Caputi A P

机构信息

Institute of Pharmacology, School of Medicine, University of Messina, Italy.

出版信息

Br J Pharmacol. 1999 May;127(2):498-504. doi: 10.1038/sj.bjp.0702528.

DOI:10.1038/sj.bjp.0702528

PMID:10385251

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1566016/

Abstract

Tumour necrosis factor (TNF-alpha) is a pleiotropic cytokine which is deeply involved in the pathogenesis of splanchnic artery occlusion (SAO) shock. Tacrolimus, formerly known as FK506, is a macrolide antibiotic, that blocks the transcription of several proinflammatory cytokines including TNF-alpha. 2. Male anaesthetized rats were subjected to clamping of the splanchnic arteries for 45 min. This surgical procedure resulted in an irreversible state of shock (SAO shock). Sham operated animals were used as controls. SAO shocked rats had a decreased survival rate (0% at 4 h of reperfusion, while sham shocked rats survived more than 4 h), enhanced serum TNF-alpha concentrations (415+/-12 U ml(-1)), decreased mean arterial blood pressure (MAP), leukopenia and increased ileal leukocyte accumulation studied by means of myeloperoxidase activity (MPO=7.5+/-0.3 U g(-1) tissue). Moreover aortic rings from shocked rats showed a marked hyporeactivity to phenylephrine (PE, 1 nM - 10 microM), reduced responsiveness to acetylcholine (ACh, 10 nM - 10 microM) and increased staining for intercellular adhesion molecule-1 (ICAM-1). Furthermore increased mRNA for TNF-alpha was observed in peritoneal macrophages of SAO shocked rats. 3. Tacrolimus (100 microg kg(-1), 5 min after splanchnic arteries occlusion) increased survival rate (SAO + Tacrolimus = 100% at 4 h of reperfusion), reverted 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), restored to control values the hyporeactivity to PE. improved the reduced responsiveness to ACh and blunted the enhanced immunostaining for ICAM-1 in the 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.

摘要

肿瘤坏死因子（TNF-α）是一种多效性细胞因子，它在腹腔动脉闭塞（SAO）性休克的发病机制中起重要作用。他克莫司，原称FK506，是一种大环内酯类抗生素，可阻断包括TNF-α在内的多种促炎细胞因子的转录。2. 将雄性麻醉大鼠的腹腔动脉夹闭45分钟。该手术操作导致不可逆的休克状态（SAO休克）。假手术动物用作对照。SAO休克大鼠的存活率降低（再灌注4小时时为0%，而假休克大鼠存活超过4小时），血清TNF-α浓度升高（415±12 U/ml），平均动脉血压（MAP）降低，白细胞减少，通过髓过氧化物酶活性研究发现回肠白细胞积聚增加（MPO = 7.5±0.3 U/g组织）。此外，休克大鼠的主动脉环对去氧肾上腺素（PE，1 nM - 10 μM）表现出明显的反应性降低，对乙酰胆碱（ACh，10 nM - 10 μM）的反应性降低，细胞间黏附分子-1（ICAM-1）染色增加。此外，在SAO休克大鼠的腹腔巨噬细胞中观察到TNF-α的mRNA增加。3. 他克莫司（腹腔动脉闭塞后5分钟，100 μg/kg）提高了存活率（SAO + 他克莫司在再灌注4小时时为100%），逆转了明显的低血压，降低了血清TNF-α（15±3 U/ml），改善了白细胞减少，降低了回肠MPO（0.9±0.01 U/g组织），使对PE的反应性降低恢复到对照值，改善了对ACh的反应性降低，并减弱了主动脉中ICAM-1增强的免疫染色。最后，他克莫司抑制了腹腔巨噬细胞中的细胞因子mRNA水平。4. 数据表明他克莫司可能代表循环性休克的一种新的治疗方法。