Dysfunctional intracellular trafficking in the pathobiology of pulmonary arterial hypertension.
Dysfunctional intracellular trafficking in the pathobiology of pulmonary arterial hypertension.
复制标题
肺动脉高压病理学中细胞内运输功能失调。
DOI：
10.1165/rcmb.2007-0066tr
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发表时间：
2007
影响因子：
6.4
通讯作者：
Mukhopadhyay,Somshuvra
中科院分区：
文献类型：
--
作者：
Sehgal,PravinB;Mukhopadhyay,Somshuvra
在人类和实验模型中，关于肺动脉高压（PAH）发生的讨论主要集中在中型肺动脉的内膜和中膜增生。认为组织学事件包括扩大的空泡化内皮细胞的无序增殖、受影响血管的新肌化和血管修剪。家族性和散发性PAH与BMPR 2突变相关性的发现引起了人们对内皮细胞中细胞因子受体运输和功能以及如何破坏这些功能以产生扩大的增殖细胞表型的强烈兴趣。然而，在PAH的病理生物学的讨论中，很大程度上没有考虑到内皮细胞中膜运输的亚细胞机制以及这种向外和向内膜运输中断的后果。PAH领域的长期电子显微镜数据表明，人类和实验性PAH的细胞内膜运输明显中断。此外，膜运输调节Nef在猴HIV诱导的猕猴PAH和HIV诱导的人类PAH中的作用现在是显而易见的。此外，已知野百合碱和缺氧会破坏高尔基体系链、SNARE、SNAP和N-乙基马来酰亚胺敏感因子的功能（“高尔基体阻断假说”）。这些结果，沿着最近的报告表明，在高尔基体中的PAH相关的人类BMPR 2突变体的陷阱，突出了破坏的细胞内膜运输的PAH的病理生物学的影响。这篇综述的目的是简要概述细胞内运输的分子基础，并将这些考虑因素与PAH的病理生物学联系起来。
Discussions of the initiation of pulmonary arterial hypertension (PAH) in man and in experimental models have centered around intimal and medial proliferation in medium-sized pulmonary arteries. The histologic events are thought to include disordered proliferation of enlarged, vacuolated endothelial cells, neo-muscularization of the affected blood vessels, and vascular pruning. The discovery of the association of familial and sporadic PAH with mutations inBMPR2has generated intense interest in cytokine receptor trafficking and function in the endothelial cell and how this might be disrupted to yield an enlarged proliferative cell phenotype. Nevertheless, considerations of the subcellular machinery of membrane trafficking in the endothelial cell and consequences of the disruption of this outward and inward membrane trafficking are largely absent from discussions of the pathobiology of PAH. Long-standing electron microscopy data in the PAH field has demonstrated marked disruptions of intracellular membrane trafficking in human and experimental PAH. Further, a role of the membrane-trafficking regulator Nef in simian HIV-induced PAH in macaques and in HIV-induced PAH in man is now evident. Additionally, monocrotaline and hypoxia are known to disrupt the function of Golgi tethers, SNAREs, SNAPs, and N-ethylmaleimide–sensitive factor (“the Golgi blockade hypothesis”). These results, along with recent reports demonstrating the trapping of PAH-associated human BMPR2 mutants in the Golgi, highlight the implications of disrupted intracellular membrane trafficking in the pathobiology of PAH. The purpose of this review is to present a brief overview of the molecular basis of intracellular trafficking and relate these considerations to the pathobiology of PAH.