Dexamethasone diminishes the pro-inflammatory and cytotoxic effects of amyloid beta-protein in cerebrovascular smooth muscle cells.
Dexamethasone diminishes the pro-inflammatory and cytotoxic effects of amyloid beta-protein in cerebrovascular smooth muscle cells.
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DOI：
10.1186/1742-2094-3-18
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发表时间：
2006-08-03
影响因子：
9.3
通讯作者：
Van Nostrand WE
中科院分区：
文献类型：
--
作者：
Previti ML;Zhang W;Van Nostrand WE
纤维状淀粉样β蛋白（Aβ）的脑血管沉积（称为脑淀粉样血管病（CAA））是阿尔茨海默病（AD）及相关疾病的显著病理特征。脑血管纤维Aβ的蓄积与促进局部神经炎症有关，导致平滑肌细胞显著变性，并可导致血管壁完整性丧失伴出血。然而，脑血管纤维Aβ诱导的炎症反应与血管壁局部细胞毒性之间的关系仍不清楚。类固醇类抗炎药，如地塞米松，据报道，以减少与CAA相关的神经炎症和出血。然而，关于CAA中的局部炎症和出血，甾体抗炎药治疗的有益作用的基础尚不清楚。培养的人脑血管平滑肌细胞系统是研究Aβ在CAA中致病作用的理想体外模型。为了检查地塞米松可能影响CAA诱导的细胞病理学的可能性，我们研究了这种抗炎剂对HCSM细胞对Aβ的炎症和细胞毒性反应的影响。在存在或不存在甾体抗炎药地塞米松或非甾体抗炎药吲哚美辛或布洛芬的情况下，用或不用致病性Aβ处理HCSM细胞的原代培养物。使用荧光活细胞/死细胞测定法测量细胞活力。采用定量免疫印迹法测定细胞表面Aβ和淀粉样β蛋白前体（AβPP）积聚量以及血管平滑肌细胞α肌动蛋白丢失量。为了评估炎症的程度，通过ELISA测量分泌的白细胞介素-6（IL-6）水平，并且通过明胶酶谱法评估活性基质金属蛋白酶-2（MMP-2）水平。地塞米松可显著降低致病性Aβ诱导的HCSM细胞死亡，但布洛芬或吲哚美辛不影响其作用。地塞米松对Aβ的初始致病作用（包括HCSM细胞表面结合、细胞表面纤维样组装和细胞表面AβPP蓄积）无影响。然而，地塞米松显著减轻了Aβ治疗的晚期病理结果（与炎症和细胞变性相关，包括IL-6水平升高、MMP-2活化和HCSM α肌动蛋白丢失），但吲哚美辛或布洛芬未减轻。我们的研究结果表明，虽然地塞米松对HCSM细胞表面纤维状Aβ积聚没有明显的影响，但它有效地减少了随后的病理反应，包括IL-6水平升高，MMP-2活化和HCSM α肌动蛋白耗竭。与吲哚美辛或布洛芬不同，地塞米松可能会减少这些病理过程，这些病理过程可能会导致炎症和血管壁完整性丧失，从而导致CAA出血。
Cerebrovascular deposition of fibrillar amyloid β-protein (Aβ), a condition known as cerebral amyloid angiopathy (CAA), is a prominent pathological feature of Alzheimer's disease (AD) and related disorders. Accumulation of cerebral vascular fibrillar Aβ is implicated in promoting local neuroinflammation, causes marked degeneration of smooth muscle cells, and can lead to loss of vessel wall integrity with hemorrhage. However, the relationship between cerebral vascular fibrillar Aβ-induced inflammatory responses and localized cytotoxicity in the vessel wall remains unclear. Steroidal-based anti-inflammatory agents, such as dexamethasone, have been reported to reduce neuroinflammation and hemorrhage associated with CAA. Nevertheless, the basis for the beneficial effects of steroidal anti-inflammatory drug treatment with respect to local inflammation and hemorrhage in CAA is unknown. The cultured human cerebrovascular smooth muscle (HCSM) cell system is a useful in vitro model to study the pathogenic effects of Aβ in CAA. To examine the possibility that dexamethasone may influence CAA-induced cellular pathology, we investigated the effect of this anti-inflammatory agent on inflammatory and cytotoxic responses to Aβ by HCSM cells. Primary cultures of HCSM cells were treated with or without pathogenic Aβ in the presence or absence of the steroidal anti-inflammatory agent dexamethasone or the non-steroidal anti-inflammatory drugs indomethacin or ibuprofen. Cell viability was measured using a fluorescent live cell/dead cell assay. Quantitative immunoblotting was performed to determine the amount of cell surface Aβ and amyloid β-protein precursor (AβPP) accumulation and loss of vascular smooth cell α actin. To assess the extent of inflammation secreted interleukin-6 (IL-6) levels were measured by ELISA and active matrix metalloproteinase-2 (MMP-2) levels were evaluated by gelatin zymography. Pathogenic Aβ-induced HCSM cell death was markedly reduced by dexamethasone but was unaffected by ibuprofen or indomethacin. Dexamethasone had no effect on the initial pathogenic effects of Aβ including HCSM cell surface binding, cell surface fibril-like assembly, and accumulation of cell surface AβPP. However, later stage pathological consequences of Aβ treatment associated with inflammation and cell degeneration including increased levels of IL-6, activation of MMP-2, and loss of HCSM α actin were significantly diminished by dexamethasone but not by indomethacin or ibuprofen. Our results suggest that although dexamethasone has no appreciable consequence on HCSM cell surface fibrillar Aβ accumulation it effectively reduces the subsequent pathologic responses including elevated levels of IL-6, MMP-2 activation, and depletion of HCSM α actin. Dexamethasone, unlike indomethacin or ibuprofen, may diminish these pathological processes that likely contribute to inflammation and loss of vessel wall integrity leading to hemorrhage in CAA.
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影响因子：
105.7
作者：
Etminan, M;Gill, S;Samii, A
通讯作者：
Samii, A
影响因子：
30.8
作者：
HENDRIKS, L;VANDUIJN, CM;VAN BROECKHOVEN, C
通讯作者：
VAN BROECKHOVEN, C
影响因子：
4.7
作者：
Jung, SS;Zhang, WB;Van Nostrand, WE
通讯作者：
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影响因子：
5.1
作者：
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通讯作者：
Lennox, GG
DOI：
10.1097/00005072-199703000-00006
发表时间：
1997-03-01
影响因子：
3.2
作者：
MaatSchieman, MLC;vanDuinen, SG;Roos, RAC
通讯作者：
Roos, RAC