巨噬细胞- NLRP3激活促进肺动脉高压中右心室衰竭

2022-06-18 刘少飞 MedSci原创

右心室巨噬细胞中NLRP3炎症体激活途径对肺动脉高压(PAH)发展到RV衰竭(RVF)的病理学重要性。PAH中的RVF是由巨噬细胞炎症体激活驱动的。

肺动脉高压(PAH)经常导致右心室衰竭(RVF)而死亡。目前的理论认为,从代偿期到失代偿期的过渡 RVH主要是由肺血管疾病和RV后负荷的发展造成的。我们的工作挑战了这一教条,并提出了房室炎症在控制 PAH中不利的RV重塑和功能障碍的关键作用。NLRP3-巨噬细胞活化可能促进 PAH 中的 RVF。

研究目的:

评估 RV 巨噬细胞中的 NLRP3 炎性体对 PAH-RVF 的贡献。

研究方法:

将失代偿性 RV 肥大 (RVH) [野百合碱 (MCT) 和 Sugen-5416 缺氧 (SuHx)] 大鼠与代偿 RVH 大鼠 [肺动脉束带 (PAB)] 进行比较。进行了超声心动图和右心导管检查。通过显微镜或流式细胞术评估巨噬细胞、心房利钠肽 (ANP) 和纤维化。NLRP3 炎性体激活和心脏毒性通过免疫印迹和体外策略得到证实。用 SC-144(一种 GP130 拮抗剂)和 MCC950(一种 NLRP3 抑制剂)治疗 MCT 大鼠。在 PAH-RVF 患者中评估巨噬细胞-NLRP3 活性。

测量结果和主要结果:

MCT 和 SuHx-RVs 的巨噬细胞、纤维化和 ANP 增加,但 LV 或 PAB 大鼠没有增加。MCT-RV 巨噬细胞具有炎症性,而肺巨噬细胞具有抗炎性。CCR2+ 巨噬细胞(单核细胞衍生)在 MCT-和 SuHx-RV 中增加,并且 NLRP3 高表达。PAH 患者失代偿的 RV 中巨噬细胞-NLRP3 通路上调。培养的 MCT 单核细胞显示 NLRP3 活化,并且在共培养实验中导致心肌细胞线粒体损伤,而 MCC950 可以防止这种损伤。在体内,MCC950 减少了 NLRP3 的激活并消退了肺血管疾病和 RVF。SC-144 降低了 RV 巨噬细胞和 NLRP3 含量,阻止了 STAT3 激活,并改善了 RV 功能,而不会使肺血管疾病消退。

研究结论:

NLRP3-巨噬细胞活化发生在临床前 PAH 模型和 PAH 患者的失代偿 RV 中。抑制 GP130 或 NLRP3 信号可改善 RV 功能。PAH-RVF 是由 RV 炎症引起的,而不仅仅是由 RV 后负荷升高引起的这一概念表明了一种新的治疗范式。

本研究启示:

这项研究的结果揭示了右心室巨噬细胞中NLRP3炎症体激活途径对肺动脉高压(PAH)发展到RV衰竭(RVF)的病理学重要性。我们挑战传统的观点,即RVF主要是由PVR增加引起的,通过治疗RV炎症,以减少RV-巨噬细胞的积累(GP130拮抗剂,SC-144)和NLRP3炎症体的激活(MCC950),独立于肺部血管。

 

参考文献:

Al-Qazazi R, Lima PDA, Prisco SZ, Potus F, Dasgupta A, Chen KH, Tian L, Bentley RE, Mewburn J, Martin AY, Wu D, Jones O, Maurice DH, Bonnet S, Provencher S, Prins KW, Archer SL. Macrophage-NLRP3 Activation Promotes Right Ventricle Failure in Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 2022 Jun 14. doi: 10.1164/rccm.202110-2274OC. Epub ahead of print. PMID: 35699679.

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    2022-06-20 huaguang

    炎性激活和心脏毒性导致心衰加重

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    2022-06-17 yuandd
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    2022-06-17 vera_1207
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