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肿瘤坏死因子-α介导的脑动脉瘤炎症:与生长和破裂的潜在联系

TNF-alpha-mediated inflammation in cerebral aneurysms: a potential link to growth and rupture.

作者信息

Jayaraman Thottala, Paget Andrew, Shin Yang Sam, Li Xiaguai, Mayer Jillian, Chaudhry Hinaw, Niimi Yasunari, Silane Michael, Berenstein Alejandro

机构信息

Department of Neurosurgery, St. Luke's Roosevelt Hospital Center, New York, NY 10025, USA.

出版信息

Vasc Health Risk Manag. 2008;4(4):805-17. doi: 10.2147/vhrm.s2700.

Abstract

Intracranial aneurysm (IA) rupture is one of the leading causes of stroke in the United States and remains a major health concern today. Most aneurysms are asymptomatic with a minor percentage of rupture annually. Regardless, IA rupture has a devastatingly high mortality rate and does not have specific drugs that stabilize or prevent aneurysm rupture, though other preventive therapeutic options such as clipping and coiling of incidental aneurysms are available to clinicians. The lack of specific drugs to limit aneurysm growth and rupture is, in part, attributed to the limited knowledge on the biology of IA growth and rupture. Though inflammatory macrophages and lymphocytes infiltrate the aneurysm wall, a link between their presence and aneurysm growth with subsequent rupture is not completely understood. Given our published results that demonstrate that the pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), is highly expressed in human ruptured aneurysms, we hypothesize that pro-inflammatory cell types are the prime source of TNF-alpha that initiate damage to endothelium, smooth muscle cells (SMC) and internal elastic lamina (IEL). To gain insights into TNF-alpha expression in the aneurysm wall, we have examined the potential regulators of TNF-alpha and report that higher TNF-alpha expression correlates with increased expression of intracellular calcium release channels that regulate intracellular calcium (Ca2+), and Toll like receptors (TLR) that mediate innate immunity. Moreover, the reduction of tissue inhibitor of metalloproteinase-1 (TIMP-1) expression provides insights on why higher matrix metalloproteinase (MMP) activity is noted in ruptured IA. Because TNF-alpha is known to amplify several signaling pathways leading to inflammation, apoptosis and tissue degradation, we will review the potential role of TNF-alpha in IA formation, growth and rupture. Neutralizing TNF-alpha action in the aneurysm wall may have a beneficial effect in preventing aneurysm growth by reducing inflammation and arterial remodeling.

摘要

颅内动脉瘤(IA)破裂是美国中风的主要原因之一,至今仍是一个重大的健康问题。大多数动脉瘤无症状,每年只有一小部分会破裂。尽管如此,IA破裂的死亡率极高,且尚无稳定或预防动脉瘤破裂的特效药物,不过临床医生可采用其他预防性治疗方法,如对偶然发现的动脉瘤进行夹闭和栓塞。缺乏限制动脉瘤生长和破裂的特效药物,部分原因是对IA生长和破裂生物学的了解有限。尽管炎性巨噬细胞和淋巴细胞浸润动脉瘤壁,但其存在与动脉瘤生长及随后破裂之间的联系尚未完全明确。鉴于我们已发表的结果表明促炎细胞因子肿瘤坏死因子-α(TNF-α)在人类破裂动脉瘤中高表达,我们推测促炎细胞类型是TNF-α的主要来源,它引发对内皮细胞、平滑肌细胞(SMC)和内弹性膜(IEL)的损伤。为深入了解TNF-α在动脉瘤壁中的表达,我们研究了TNF-α的潜在调节因子,并报告更高的TNF-α表达与调节细胞内钙(Ca2+)的细胞内钙释放通道以及介导先天免疫的Toll样受体(TLR)表达增加相关。此外,金属蛋白酶组织抑制剂-1(TIMP-1)表达的降低为为何在破裂IA中观察到更高的基质金属蛋白酶(MMP)活性提供了线索。由于已知TNF-α会放大导致炎症、细胞凋亡和组织降解的多种信号通路,我们将综述TNF-α在IA形成、生长和破裂中的潜在作用。中和动脉瘤壁中TNF-α的作用可能通过减轻炎症和动脉重塑对预防动脉瘤生长产生有益影响。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e499/2597764/b67866fbbd09/vhrm-4-0805f1.jpg

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