Cardiovascular Disease Theme, Monash Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Melbourne, Victoria, Australia.
Cardiovascular Disease Theme, Monash Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Melbourne, Victoria, Australia.
Pharmacol Ther. 2020 May;209:107511. doi: 10.1016/j.pharmthera.2020.107511. Epub 2020 Feb 22.
Cardiovascular fibrosis refers to the scar tissue that develops in the injured heart and blood vessels from an aberrant wound healing response to organ injury or insult. Established fibrosis becomes a hallmark of chronic disease progression and a key contributor to tissue stiffness and dysfunction, which ultimately leads to heart failure. As wound healing and fibrotic responses to myocardial injury are multifactorial processes, current therapies that only target specific contributing factors to disease pathogenesis offer limited overall anti-fibrotic efficacy. As such, recent attention has turned to targeting the body's immune system, which orchestrates the wound healing response to tissue injury. This review focuses on the increasing body of work that has identified the NLRP3 inflammasome, a multiprotein oligomer complex responsible for activation of inflammatory responses via its production of IL-1β and IL-18, as an immune system-initiated facilitator of cardiovascular healing, but also an important contributor to tissue scarring following its persistent activation. The review summarises the factors that can elicit priming and activation of the inflammasome complex, how the activated inflammasome complex contributes to cardiovascular pathophysiology and fibrosis progression, and the molecular mechanisms involved from various cell culture and animal model studies that have utilised genetic deletion or pharmacological inhibition of specific components of the inflammasome. Finally, it outlines currently known and previously unrecognised cardiovascular receptors that may be pharmacologically targeted to ablate the contribution of the NLRP3 inflammasome to cardiovascular diseases characterised by fibrosis, by compounds that may be developed as effective adjunct therapies to current standard of care medication.
心血管纤维化是指在器官损伤或损伤后，异常的伤口愈合反应在受伤的心脏和血管中产生的疤痕组织。已建立的纤维化成为慢性疾病进展的标志，也是组织僵硬和功能障碍的主要原因，最终导致心力衰竭。由于伤口愈合和纤维化反应是多因素的过程，目前仅针对疾病发病机制的特定致病因素的治疗方法提供的整体抗纤维化效果有限。因此，最近的注意力转向了靶向身体的免疫系统，免疫系统协调对组织损伤的伤口愈合反应。本综述重点介绍了越来越多的工作，这些工作已经确定了 NLRP3 炎性体，这是一种多蛋白寡聚体复合物，通过其产生的 IL-1β 和 IL-18 负责激活炎症反应，作为免疫系统启动的心血管愈合促进剂，但也是持续激活后组织瘢痕形成的重要贡献者。该综述总结了可以引发炎性体复合物的引发和激活的因素，激活的炎性体复合物如何促进心血管病理生理学和纤维化进展，以及涉及各种细胞培养和动物模型研究的分子机制，这些研究利用炎性体的特定成分的基因缺失或药理学抑制。最后，它概述了目前已知和以前未被识别的心血管受体，这些受体可能通过药理学靶向来消除 NLRP3 炎性体对纤维化特征的心血管疾病的贡献，通过可能开发为当前标准治疗药物的有效辅助治疗的化合物。
