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Youmans:顱內動脈瘤-2

WCH | 2021-07-27 19:57:55 | 巴幣 1118 | 人氣 306


動脈瘤壁分解與破裂的機轉

  • In normal arteries, myointimal hyperplasia is an adaptive mechanism in response to hemodynamic stress or mechanical injury. Pads of myointimal hyperplasia are formed when endothelial damage from injury or stress induces a change in the phenotype of medial smooth muscle cells that promotes their migration to and proliferation at the damaged endothelial lining. The histopathologic resemblance of unruptured intracranial aneurysm walls to myointimal hyperplasia suggests that the aneurysm wall reacts similarly to hemodynamic stress by increasing cell proliferation and matrix synthesis. However, it is still unclear whether the myointimal hyperplasia in aneurysms is an adaptive mechanism of the vascular wall to compensate for excessive stress or whether it contributes to weakening of the wall. Unlike terminally differentiated skeletal and cardiac muscle cells, arterial smooth muscle cells can change in phenotype. In cerebral aneurysms, the smooth muscle cells go from a “contraction”-oriented phenotype to a “proinflammatory and matrix remodeling” phenotype, which suggests that alterations in smooth muscle cells play a role in pathogenesis.
在正常的動脈裡面,肌肉型內膜是一個為了對抗血液動力造成的壓力或是動脈壁受損,所形成的構造。一旦上皮細胞因為受傷或是壓力而受損,中膜的平滑肌就會增生到受損的內皮細胞進而形成肌肉型內膜。
組織學發現未破損的動脈瘤壁跟肌肉型內膜成分類似,因此推論可能是因為動脈瘤壁同樣因為血液動力的壓力而促進細胞增生和細胞基質的合成。但對於動脈瘤的肌肉型內膜能不能讓血管壁更能承受壓力,抑或是造成血管壁弱化,還沒有定論。
跟其他骨骼肌和心肌不同,動脈的平滑肌細胞型態是可以改變的。在大腦的動脈瘤,平滑肌細胞可以從「收縮功能為主」的型態,轉變成「發炎前和細胞基質重組」的型態,可能跟病理表現有關。
  • Results of histologic studies suggest that intracranial aneurysm walls rupture as a consequence of matrix degeneration and decellularization, which may be the result of direct vascular stress or injury or may correspond to defects in homeostatic maintenance or repair mechanisms. Although it is still unclear how risk factors for subarachnoid hemorrhage—such as smoking, hypertension, female gender, previous subarachnoid hemorrhage, and age—contribute to rupture, data suggest that proteolysis, programmed cell death, inflammation, and hemodynamic stress are associated with aneurysm wall degeneration and rupture.
組織學研究發現顱內動脈瘤壁的破裂是因為細胞基質的分解和去細胞化所造成。可能是因為血管因為壓力或受傷而造成細胞基質無法維持同化或修復功能。雖然對於蜘蛛膜下腔出血(註:動脈瘤破裂為主因)的危險因子成因還不清楚(抽菸、高血壓、女性、過去蜘蛛膜下腔出血病史或是年紀),研究資料卻顯示蛋白水解、有計畫的細胞死亡、發炎以及血液動力的壓力跟動脈瘤破裂相關。

蛋白水解和顱內動脈瘤

  • Extracellular matrix components are constantly being synthesized and degraded. In comparison with normal intracranial arteries, aneurysm tissue, especially ruptured aneurysm tissue, displays increased activity or expression (or both) of matrix-degrading proteases that regulate remodeling of the arterial wall. Prominent in aneurysm walls are matrix metalloproteinase (MMP)–2 and MMP-9, which are classified as gelatinases and are capable of degrading both elastin and denatured collagen. In a series of 23 patients with intracranial aneurysms, Bruno and associates found focal areas of gelatinase activity attributable to MMP-2 and MMP-9 in both ruptured and unruptured aneurysms. Increased protease activity correlated with increased expression of MMP-2, plasmin, and membrane-type MMP, the latter two being involved in activation of MMP-2. Increased serum levels of elastase have also been observed in patients with aneurysms. Furthermore, cathepsin D–expressing cells have been found in aneurysm walls in regions where the collagen layer was degraded. Cathepsin D is an endopeptidase that can also digest extracellular matrix proteins.
細胞外基質的成分一直受到合成與分解。跟正常的顱內動脈相比,動脈瘤尤其是已經破裂的,發現細胞基質分解蛋白酵素是增加的。在動脈瘤壁主要的是MMP-2和MMP-9,這些是可以分解明膠的酵素,能夠把彈性蛋白和膠原蛋白給分解掉。一個研究23位動脈瘤病人的文獻發現無論有沒有破裂,都有MMP-2和MMP-9的活性存在。蛋白分解酵素主要跟MMP-2、纖維溶解酵素和細胞膜型態MMP的表現有關。後兩者跟MMP-2的活化有關。此外組織蛋白酵素D表現細胞也在膠原蛋白被分解的動脈瘤中被發現,它也能分解細胞外基質蛋白。
  • Data suggest that increased proteolysis may also contribute to rupture of intracranial aneurysms. In a series of 30 patients with aneurysms, Jin and colleagues found that messenger RNA (mRNA) levels of MMP-2 and MMP-9 were higher in ruptured aneurysms than in unruptured aneurysms. Levels of MMP-2 and MMP-9 were elevated in relation to their inhibitors (called tissue inhibitors of MMPs [TIMPs]) in ruptured aneurysms. Patients with ruptured aneurysms had higher serum MMP-2 and MMP-9 levels than did those with unruptured aneurysms. Upregulation of elastase activity has also been observed in the arterial walls of ruptured aneurysms, in comparison with unruptured aneurysms.
研究也發現蛋白溶解的增加跟動脈瘤破裂有關。一個30位動脈瘤病患的研究發現已經破裂的動脈瘤比未破裂的還要更多MMP-2和MMP-9的mRNA。同時血清中破裂的MMP-2和MMP-9含量也比未破裂的多。在已破裂的動脈瘤也被發現彈性蛋白分解酵素比未破裂的還要高。

自體凋亡和動脈瘤

  • Very few cells undergo programmed cell death (apoptosis) in normal arterial wall tissue. In contrast, many apoptotic cells are found in intracranial aneurysm walls, especially in ruptured aneurysms. Experimental and clinical studies have shown that the decreased number of smooth muscle cells in aneurysm walls is caused primarily by apoptosis. Higher apoptosis levels were also found in the meningeal and superficial temporal arteries in patients with ruptured aneurysms than in patients with unruptured lesions.  In a series of five ruptured aneurysms, Hara and coworkers found that many apoptotic cells were localized in the neck and dome of aneurysms, close to the rupture point, whereas no apoptosis was detected in control arteries. These results suggest that apoptosis plays an important role in the development and rupture of intracranial aneurysms.
正常的動脈壁不太有細胞凋亡,但在顱內動脈瘤壁上卻很多,尤其是已破裂的。研究已經發現在動脈瘤中會有平滑肌因為細胞凋亡而變少的情況。同時在已破裂動脈瘤患者也可以在腦膜動脈和淺層顳動脈發現細胞自體凋亡的比例,比未破裂的病患還要增加。在一個五階段的實驗中發現在動脈瘤的頸部和頂部都有很多的自體凋亡細胞,而這些地方也很接近破裂點。這結果認為顱內動脈瘤破裂跟自體凋亡有關。
  • The events that trigger apoptosis in aneurysm walls are unclear. It had been proposed that apoptosis is induced by cytokines released by inflammatory cells that infiltrate aneurysm tissues. Jayaraman and associates showed that mRNA and protein expression of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) and its proapoptotic downstream target, Fas-associated death domain protein, are increased in ruptured aneurysms, which suggests that TNF-α has a role in promoting inflammation and subsequent apoptosis in aneurysm walls.
至於為甚麼會造成細胞自體凋亡還不清楚,可能是因為發炎細胞釋出細胞激素(註:增加發炎反應的物質)導致動脈瘤組織大量浸潤。研究發現發炎前細胞激素TNF-α還有它的下游目標,偶聯死亡區域蛋白Fas在破裂的動脈瘤中都有增加的趨勢。認為可能是TNF-α造成細胞自體凋亡。
  • A role for the c-Jun amino-terminal kinase (JNK) pathway in apoptosis in intracranial aneurysms has also been proposed. Inflammatory signals are capable of stimulating JNK (a member of the mitogen-activated protein kinase family) to initiate apoptosis through phosphorylation of the c-Jun transcription factor. In a series of 12 intracranial aneurysms and 5 control vessels, Takagi and coworkers found that phosphorylation of JNK and its target, c-Jun, was increased in aneurysm tissues in regions where apoptosis in smooth muscle cells was also increased. In a series of 12 ruptured and 12 unruptured aneurysms, Laaksamo and associates found that JNK phosphorylation in the RNA-binding protein p54 was 1.5-fold higher in ruptured aneurysms than in unruptured aneurysms. Furthermore, phosphorylation of p54 JNK and the protein levels of both JNK and c-Jun were found to be correlated with aneurysm size.
JNK路徑也在細胞自體凋亡中被提出來。發炎反應會刺激JNK路徑然後透過c-Jun因子的磷酸裂解而活化。在一個拿12位動脈瘤患者和5名正常實驗者的研究中發現JNK和c-Jun在動脈瘤中都有增加,而增加的區域都發現平滑肌細胞也更加自體凋亡。另一個拿12位破裂的動脈瘤患者和12名未破裂的研究中發現JNK p54蛋白的磷酸裂解前者比後者高出1.5倍。同時他們也發現JNK p54蛋白和JNK、c-Jun蛋白的量跟動脈瘤大小有關係。

發炎和動脈瘤

  • The presence of macrophages, T cells, B cells, immunoglobulin antibodies, and activated complement in intracranial aneurysm walls, especially in ruptured aneurysms, indicates that active innate and adaptive immunologic reactions are associated with aneurysm formation and rupture. Upregulated expression of the proinflammatory chemokine monocyte chemoattractant protein-1 in the aneurysm wall has also been observed. Even though mRNA of monocyte chemoattractant protein-1 was not detectable in normal arteries, it was often observed in the intima of aneurysmal walls and appeared to be expressed in the cytoplasm of fibroblast cells that assembled with monocyte-like cells. The extent of inflammatory cell infiltration and complement activation appeared to be higher in ruptured aneurysms than in unruptured aneurysms.
免疫的巨噬細胞、T細胞、B細胞和免疫球蛋白抗體活躍於動脈瘤壁上面,尤其是在已經破裂的動脈瘤。可以說免疫反應跟動脈瘤的形成和破裂是有關係的。發炎前細胞激素MCP-1也被發現在動脈瘤上有增加的趨勢,反觀在正常動脈中連MCP-1的mRNA都不會出現。在動脈瘤內膜的纖維母細胞和似單核球細胞的細胞質中都常會發現MCP-1的mRNA。在破裂的動脈瘤比未破裂的還要更多發炎細胞的浸潤與活化。
  • Further evidence of the development of active immune reactions in intracranial aneurysm specimens was demonstrated in a microarray study by Krischek and colleagues, who compared the global transcription profiles of six ruptured and four unruptured aneurysm tissues with the profiles of four control arteries. Genes involved in antigen presentation, such as major histocompatibility complex class II genes, emerged as those with the highest upregulation in the aneurysm samples.
更多的證據指向免疫活化反應跟顱內動脈瘤的生成有關。一個研究找了6個破裂的和4個未破裂的動脈瘤組織,外加4個正常的動脈壁組織。發現跟免疫抗體相關的基因,例如主要的第二類MHC,在動脈瘤中都有很高的表現。

創作回應

銘叔
我看的當下還以為我的英文超破,後來才發現原來都是專有名詞。
2021-07-27 21:15:43
WCH
哈哈醫學很多專有名詞呢~
2021-07-27 22:01:16
阿飛
請問要預防顱內動脈瘤要做什麼檢查?
2021-07-29 08:54:54
WCH
如果是高危險群,例如上訴危險因子或是有家族史,可以考慮做核磁共振檢查
2021-07-29 08:56:21
阿飛
明白感謝
2021-07-29 09:09:14
WCH
不客氣呢!
2021-07-29 21:15:35

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