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New Molecular Targets of Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension Importance of Endothelial Communication

机译:肺血管重塑在肺动脉高压中重要作用的新分子靶点

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Pulmonary arterial hypertension (PAH) is a disorder in which mechanical obstruction of the pulmonary vascular bed is largely responsible for the rise in mean pulmonary arterial pressure, resulting in a progressive functional decline despite current available therapeutic options. The fundamental pathogenetic mechanisms underlying this disorder include pulmonary vasoconstriction, in situ thrombosis, medial hypertrophy, and intimal proliferation, leading to occlusion of the small to mid-sized pulmonary arterioles and the formation of plexiform lesions. Several predisposing or promoting mechanisms that contribute to excessive pulmonary vascular remodeling in PAH have emerged, such as altered crosstalk between cells within the vascular wall, sustained inflammation and dysimmunity, inhibition of cell death, and excessive activation of signaling pathways, in addition to the impact of systemic hormones, local growth factors, cytokines, transcription factors, and germline mutations. Although the spectrum of therapeutic options for PAH has expanded in the last 20 years, available therapies remain essentially palliative. However, over the past decade, a better understanding of new key regulators of this irreversible pulmonary vascular remodeling has been obtained. This review examines the state-of-the-art potential new targets for innovative research in PAH, focusing on (1) the crosstalk between cells within the pulmonary vascular wall, with particular attention to the role played by dysfunctional endothelial cells; (2) aberrant inflammatory and immune responses; (3) the abnormal extracellular matrix function; and (4) altered BMPRII/KCNK3 signaling systems. A better understanding of novel pathways and therapeutic targets will help in the designing of new and more effective approaches for PAH treatment.
机译:肺动脉高压(PAH)是一种疾病,其中肺血管床的机械性阻塞是平均肺动脉压升高的主要原因,尽管目前有可用的治疗选择,但导致进行性功能下降。该疾病的基本发病机制包括肺血管收缩,原位血栓形成,内侧肥大和内膜增生,从而导致中小尺寸的肺小动脉闭塞和丛状病变的形成。导致PAH过度肺血管重塑的几种诱因或促进机制已经出现,例如,除了影响外,血管壁内细胞之间的串扰改变,持续的炎症和免疫不良,细胞死亡的抑制以及信号通路的过度激活也被引起。全身激素,局部生长因子,细胞因子,转录因子和种系突变尽管在过去的20年中,PAH的治疗选择范围不断扩大,但可用的治疗方法仍基本上是姑息治疗。但是,在过去的十年中,人们已经对这种不可逆的肺血管重塑的新关键调节剂有了更好的了解。这篇综述探讨了PAH创新研究的最新潜在新目标,重点是:(1)肺血管壁内细胞之间的串扰,特别注意功能失调的内皮细胞所起的作用; (2)异常的炎症和免疫反应; (3)细胞外基质功能异常; (4)改变了BMPRII / KCNK3信号系统。对新途径和治疗靶点的更好理解将有助于设计新的更有效的PAH治疗方法。

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