Suzuki Satoshi, Sugawara Takafumi, Tabata Toshiharu, Oishi Hisashi, Niikawa Hiromichi, Kondo Takashi
Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
J Heart Lung Transplant. 2007 Apr;26(4):370-5. doi: 10.1016/j.healun.2006.12.008. Epub 2007 Feb 26.
Although liberalization of donor criteria may be one of the solutions to the current serious lung donor shortage, the use of non-standard donor lungs would increase the risk of post-operative complications. In the present study, we investigated the effect of sivelestat, a neutrophil elastase inhibitor, on reperfusion injury of a donor lung that was harvested from endotoxin-primed animals in a rat lung transplantation model.
Donor rats received an intraperitoneal injection of Escherichia coli endotoxin (5 mg/kg) 2 hours before lung harvesting. The donor lungs were flushed with an organ preservation solution with or without sivelestat (300 microg/ml), and the left lung was immediately transplanted to the recipient by the cuff technique.
Endotoxin priming did not cause significant lung injury before harvesting. Although these lungs looked normal macroscopically, they were found to contain numerous neutrophils in the alveolar capillaries, even after lung flushing. There was no significant difference in the neutrophil count between the lungs flushed with and without sivelestat. The endotoxin-primed donor lung without sivelestat treatment became edematous immediately after reperfusion. In addition, the recipient's native right lungs were also pathologic. Treatment with sivelestat significantly reduced injury in both the donor and the recipient's native lungs. Treatment with sivelestat also inhibited the increase in tumor necrosis factor-alpha and cytokine-induced neutrophil chemoattractant-1 levels in the recipient circulation after reperfusion.
We conclude that sivelestat could reduce lung injury after transplantation by inhibiting the deleterious burst of inflammatory reactions that are initiated by reperfusion of the lungs from endotoxin-primed rats.
尽管放宽供体标准可能是解决当前严重肺供体短缺问题的方法之一，但使用非标准供体肺会增加术后并发症的风险。在本研究中，我们在大鼠肺移植模型中研究了中性粒细胞弹性蛋白酶抑制剂西维来司他对内毒素预处理动物所获取供体肺再灌注损伤的影响。
供体大鼠在肺获取前2小时腹腔注射大肠杆菌内毒素（5毫克/千克）。用含或不含西维来司他（300微克/毫升）的器官保存液冲洗供体肺，然后通过袖套技术将左肺立即移植到受体。
内毒素预处理在获取前未引起明显的肺损伤。尽管这些肺在宏观上看起来正常，但即使在肺冲洗后，仍发现肺泡毛细血管中有大量中性粒细胞。用西维来司他冲洗的肺和未用西维来司他冲洗的肺之间中性粒细胞计数无显著差异。未经西维来司他治疗的内毒素预处理供体肺在再灌注后立即出现水肿。此外，受体的天然右肺也出现病理变化。西维来司他治疗显著减轻了供体肺和受体天然肺的损伤。西维来司他治疗还抑制了再灌注后受体循环中肿瘤坏死因子-α和细胞因子诱导的中性粒细胞趋化因子-1水平的升高。
我们得出结论，西维来司他可以通过抑制内毒素预处理大鼠肺再灌注引发的有害炎症反应爆发来减轻移植后的肺损伤。
