Schneeberger S, Hautz T, Wahl S M, Brandacher G, Sucher R, Steinmassl O, Steinmassl P, Wright C D, Obrist P, Werner E R, Mark W, Troppmair J, Margreiter R, Amberger A
D. Swarovski Research Laboratory, Department of General and Transplant Surgery, Innsbruck Medical University, Innsbruck, Austria.
Am J Transplant. 2008 Apr;8(4):773-82. doi: 10.1111/j.1600-6143.2008.02158.x. Epub 2008 Feb 19.
We investigated the role of secretory leukocyte protease inhibitor (SLPI) in ischemia/reperfusion injury in cardiac transplantation. SLPI-/- mouse hearts and wild-type (WT) controls were transplanted immediately or after 10 h of cold ischemia (CI). Recombinant SLPI (rSLPI) was added to the preservation solution or given systemically. After evaluation of myocardial performance, grafts were investigated for histology, SLPI, TNF-alpha, TGF-beta, NF-kappaB and protease expression at indicated time points. Early myocardial contraction was profoundly impaired in SLPI-/- hearts exposed to CI and associated with high intra-graft protease expression. Systemic administration of rSLPI had no effect, however, when SLPI was added to the preservation solution, myocardial contraction was restored to normal. At 10 days, inflammation, myocyte vacuolization and necrosis were significantly more severe in SLPI-/- hearts. SLPI gene expression was detected in WT mice at 12 and 24 h and was significantly higher after CI. SLPI protein was observed at 24 h and 10 days. High intra-graft concentrations of SLPI after administration of rSLPI were inversely correlated with protease levels early and TGF-beta expression late after reperfusion. SLPI plays a crucial role in early myocardial performance and postischemic inflammation after cardiac transplantation. A dual inhibitory effect on protease and TGF-beta expression might be the underlying mechanism.
我们研究了分泌型白细胞蛋白酶抑制剂（SLPI）在心脏移植缺血/再灌注损伤中的作用。将SLPI基因敲除小鼠心脏和野生型（WT）对照立即移植，或在冷缺血（CI）10小时后移植。将重组SLPI（rSLPI）添加到保存液中或进行全身给药。在评估心肌功能后，在指定时间点对移植物进行组织学、SLPI、肿瘤坏死因子-α（TNF-α）、转化生长因子-β（TGF-β）、核因子-κB（NF-κB）和蛋白酶表达的研究。暴露于CI的SLPI基因敲除小鼠心脏早期心肌收缩严重受损，且与移植物内高蛋白酶表达相关。然而，rSLPI全身给药无效，而当将SLPI添加到保存液中时，心肌收缩恢复正常。在第10天，SLPI基因敲除小鼠心脏的炎症、心肌细胞空泡化和坏死明显更严重。在WT小鼠中于12小时和24小时检测到SLPI基因表达，CI后显著升高。在24小时和10天时观察到SLPI蛋白。给予rSLPI后移植物内高浓度的SLPI与再灌注早期的蛋白酶水平及晚期的TGF-β表达呈负相关。SLPI在心脏移植后的早期心肌功能和缺血后炎症中起关键作用。对蛋白酶和TGF-β表达的双重抑制作用可能是其潜在机制。
