Targeting the NLRP3 inflammasome to reduce warm ischemic injury in donation after circulatory death heart
Targeting the NLRP3 inflammasome to reduce warm ischemic injury in donation after circulatory death heart
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DOI：
10.1111/ctr.14044
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发表时间：
2020-08-02
影响因子：
2.1
通讯作者：
Toldo, Stefano
中科院分区：
文献类型：
--
作者：
Quader, Mohammed;Mezzaroma, Eleonora;Toldo, Stefano
虽然循环死亡(DCD)心脏移植是一种新兴的临床实践，但移植心脏的主要来源仍然是脑死亡(DBD)供者。DCD过程诱导NOD样受体家族含-3(NLRP3)炎性小体的形成，NLRP3是炎症引起的心脏损伤的关键介质。抑制NLRP3炎性小体的形成对DCD心脏有保护作用。实验分5组，每组8只，分别为对照不停跳心脏供体(CBD)野生型(WT)组、DCD野生型(DCD)组、CBD NLRP3基因敲除(KO)组、DCD NLRP3KO组和DCD WT NLRP3抑制剂组。心脏被采集并在朗宁多夫系统上复活，以评估生理参数，然后进行分子分析。DCD-NLRP3抑制剂组在苏醒时给予NLRP3抑制剂(50mU/L)。与CBD-WT组相比，DCD-WT组组织中NLRP3水平高出80%。DCD WT组caspase-1活性显著升高，而KO或NLRP3抑制剂组则无明显变化。与CBD-WT组相比，DCD WT组的发展压和+/-dp/dt显著降低，P<；0.05，但DCD-NLRP3抑制剂组的DCD-NLRP3抑制剂组的DCD-NLRP3抑制剂组的发展压和+/-dp/dt无明显改变。DCD过程激活NLRP3炎症体，导致心肌损伤和功能障碍。NLRP3炎性小体抑制可减轻心肌损伤，保护DCD心功能。
While the donation after circulatory death (DCD) heart transplantation is an emerging clinical practice, the primary source of donor hearts for transplantation remains donation after brain death (DBD) donors. DCD process induces formation of NOD-like receptor family pyrin domain containing-3 (NLRP3) inflammasome, a key mediator of inflammation-driven damage to heart. Inhibition of NLRP3 inflammasome formation could be protective to DCD hearts. Five groups (n = 8 each) of mice were studied-control beating heart donor (CBD) wild-type (WT), DCD WT, CBD NLRP3 knockout (KO), DCD NLRP3 KO, and DCD WT NLRP3 inhibitor group. Hearts were procured and reanimated on a Langendorff system to assess physiologic parameters and then for molecular assays. NLRP3 inhibitor (50 mu mol/L) was administered to the DCD-NLRP3 inhibitor group at reanimation. Tissue NLRP3 levels were 80% higher in the DCD WT group compared with the CBD-WT group. Caspase-1 activity was significantly elevated in DCD WT but not in KO or NLRP3 inhibitor groups. The developed pressures and +/- dP/dt were significantly impaired in the DCD WT group compared with the CBD-WT group,P < .05, but were well preserved in DCD-NLRP3 inhibitor group. The DCD process activates the NLRP3 inflammasome, contributing to myocardial damage and dysfunction. NLRP3 inflammasome inhibition limits myocardial injury and preserves DCD heart function.