Al'Qteishat Ahmed, Gaffney John, Krupinski Jerzy, Rubio Francisco, West David, Kumar Shant, Kumar Patricia, Mitsios Nicholas, Slevin Mark
Department of Biology, Chemistry and Health Science, Manchester Metropolitan University, Liverpool, UK.
Brain. 2006 Aug;129(Pt 8):2158-76. doi: 10.1093/brain/awl139. Epub 2006 May 26.
The extent of recovery from stroke is dependent on the survival of neurons, particularly in peri-infarcted regions. Angiogenesis is critical for the development of new microvessels and leads to re-formation of collateral circulation, reperfusion and better recovery. Hyaluronan (HA) is an important component of the brain extracellular matrix and a regulator of cellular differentiation, migration, proliferation and angiogenesis. We have found that the production of total HA and low molecular mass 3-10 disaccharides of HA (o-HA) was increased in post-mortem tissue and in the serum of patients 1, 3, 7 and 14 days (peaking at 7 days) after ischaemic stroke. Hyaluronidase activity was also increased in serum samples (peaking after 3 days), which might explain the subsequent increase in o-HA. Affinity-histochemical staining was performed using a HA-specific biotinylated binding protein, and it showed enhanced deposition of HA in blood vessels and intracellularly as well as in the nuclei of peri-infarcted neurons. Western blotting and immunohistochemistry demonstrated upregulation of HA synthases (HAS1 and 2) and hyaluronidases (HYAL1 and 2) in inflammatory cells from both stroke and peri-infarcted regions of the brain. HYAL1 was upregulated in microvesssels and intracellularly in neurons, whilst HAS2 became translocated into the nuclei of neurons in peri-infarcted areas. Receptor for HA-mediated motility was observed intracellularly and in the nuclei of neurons, in the tunica media of larger blood vessels and in the endothelial cells of microvessels in stroke-affected tissue, whilst expression of other receptors for HA, CD44 and tumour necrosis factor-stimulated gene 6 (TSG-6) were mainly increased in infiltrating mononuclear cells from inflammatory regions. The data presented here demonstrate that HA breakdown is a feature of the acute stage of stroke injury. Increased o-HA production soon after stroke may be detrimental through enhancement of the inflammatory response, whilst activation of HA and/or o-HA-induced cellular signalling pathways in neurons and microvessels may impact on the remodelling process by stimulating angiogenesis and revascularization, as well as the survival of susceptible neurons.
中风后的恢复程度取决于神经元的存活情况，尤其是梗死周边区域的神经元。血管生成对于新微血管的发育至关重要，并导致侧支循环的重新形成、再灌注和更好的恢复。透明质酸（HA）是脑细胞外基质的重要组成部分，也是细胞分化、迁移、增殖和血管生成的调节剂。我们发现，在缺血性中风后1天、3天、7天和14天（7天达到峰值），患者的尸检组织和血清中总HA以及低分子量3-10二糖HA（o-HA）的产生增加。血清样本中的透明质酸酶活性也增加（3天后达到峰值），这可能解释了随后o-HA的增加。使用HA特异性生物素化结合蛋白进行亲和组织化学染色，结果显示HA在血管、细胞内以及梗死周边神经元的细胞核中沉积增强。蛋白质免疫印迹法和免疫组织化学法表明，中风和脑梗死周边区域的炎症细胞中HA合成酶（HAS1和2）和透明质酸酶（HYAL1和2）上调。HYAL1在微血管和神经元细胞内上调，而HAS2转移到梗死周边区域神经元的细胞核中。在中风影响的组织中，在神经元的细胞内和细胞核、较大血管的中膜以及微血管的内皮细胞中观察到HA介导的运动受体，而其他HA受体CD44和肿瘤坏死因子刺激基因6（TSG-6）的表达主要在炎症区域浸润的单核细胞中增加。此处呈现的数据表明，HA分解是中风损伤急性期的一个特征。中风后不久o-HA产生增加可能通过增强炎症反应而有害，而神经元和微血管中HA和/或o-HA诱导的细胞信号通路的激活可能通过刺激血管生成和血管再通以及易感神经元的存活来影响重塑过程。
