Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network and Department of Surgery and Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network and Department of Surgery and Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
J Heart Lung Transplant. 2018 Oct;37(10):1261-1270. doi: 10.1016/j.healun.2018.04.005. Epub 2018 Apr 26.
Increasing evidence indicates that regulated necrosis plays a critical role during cell death caused by ischemia-reperfusion (IR) injury. Necroptosis is one form of regulated necrosis. Necrostatin-1 (Nec-1), an inhibitor of receptor-interacting protein kinase 1 (RIPK1), is known to reduce necroptosis. We investigated the effect of Nec-1 treatment on IR-induced lung injury in a rat lung transplant model.
Lewis rats were divided into 4 groups (n = 6 each): (1) Control (no treatment), (2) Donor treatment (D), (3) Recipient treatment (R), and (4) Donor plus Recipient treatment (D+R) groups. Donor lungs were flushed and preserved for 18 hours at 4ºC before transplantation. Recipient animals underwent a left single lung transplant. After 2 hours of reperfusion, we assessed the physiologic function, cytokine expression, pathway activation, and the extent of necrosis.
Pulmonary gas exchange in D+R group was significantly better than in the other 3 groups (p = 0.003). Lung edema was significantly lower in the D+R group compared with the Control group (p = 0.006). The expression of interleukin-6 in lung tissue and plasma was significantly reduced in the D+R group compared with the Control group (p = 0.036). The percentage of necrotic cells in D+R group was significantly lower than in the Control and D groups (p = 0.01), indicating Nec-1inhibited regulated necrosis.
The administration of Nec-1 to both donor and recipient improved graft function after lung transplantation through the reduction of necroptosis. The inhibition of regulated necrosis appears to be a promising strategy to attenuate IR lung injury after lung transplantation.
越来越多的证据表明，程序性细胞坏死在缺血再灌注（IR）损伤引起的细胞死亡中起着关键作用。细胞程序性坏死是程序性细胞坏死的一种形式。坏死抑制剂-1（Nec-1）是一种受体相互作用蛋白激酶 1（RIPK1）的抑制剂，已知可减少细胞程序性坏死。我们在大鼠肺移植模型中研究了 Nec-1 治疗对 IR 诱导的肺损伤的影响。
将 Lewis 大鼠分为 4 组（每组 6 只）：（1）对照组（无治疗）、（2）供体治疗组（D）、（3）受体治疗组（R）和（4）供体加受体治疗组（D+R）。供体肺在移植前于 4°C 下冲洗并保存 18 小时。受体动物接受左单肺移植。再灌注 2 小时后，我们评估了生理功能、细胞因子表达、通路激活和坏死程度。
D+R 组的肺气体交换明显优于其他 3 组（p = 0.003）。与对照组相比，D+R 组的肺水肿明显降低（p = 0.006）。与对照组相比，D+R 组肺组织和血浆中白细胞介素-6 的表达明显降低（p = 0.036）。D+R 组的坏死细胞百分比明显低于对照组和 D 组（p = 0.01），表明 Nec-1 抑制了程序性坏死。
在供体和受体中给予 Nec-1 通过减少细胞程序性坏死改善了肺移植后的移植物功能。抑制程序性坏死似乎是减轻肺移植后 IR 肺损伤的一种有前途的策略。
