中老年乳腺癌患者血浆可溶性P-和E-选择素的检测及意义

研究证明：P-和E-选择素通过介导经电液转移的肿瘤细胞与血小板及血管内皮细胞的黏附在肿瘤的发生和转移过程中起重要作用。当瘤细胞与血管内皮细胞黏附时有许多黏附分子参与，如P-和E-选择素等，在进入血液循环的瘤细胞能识别靶器官血管内皮细胞的过程中起重要作用。目前，有诸多学者对P-和E-选择素在结直肠癌、肝癌等癌组织和外周血中的表达进行了研究，观点不尽相同。为探讨可溶性P-和E-选择素在中老年乳腺癌发生发展和转移中的作用，本文对57例中老年乳腺癌患者进行了两项指标的联合检测。     

P-选择素在糖尿病肾病发病中作用的研究进展

P-选择素是黏附分子家族成员,分别介导了白细胞与血小板、内皮细胞的黏附作用,作为糖尿病主要的微血管并发症,糖尿病肾病与选择素的关系密切.高糖等病理状态下,细胞信号传导途径(如PKC途径)的激活,使核转录因子κB活性增高,进而从基因水平调控P-选择素的表达.     

E-选择素与心肌缺血再灌注损伤

E-选择素是血管内皮细胞合成的一种糖蛋白分子,介导白细胞与内皮细胞的黏附过程,与炎症或缺血再灌注损伤时白细胞的募集有关。心肌缺血再灌注损伤时E-选择素表达明显增加,降低E选-择素的表达或阻断其作用可减轻缺血再灌注损伤。     

P-选择素与静脉血栓栓塞症

血小板激活是静脉血栓形成的重要组成步骤,P-选择素是血小板的活性受体,也能被上皮细胞所识别.作为血小板/内皮细胞活化标志和细胞黏附受体.其可通过介导血小板、内皮细胞黏附及与白细胞的相互作用,启动参与包括炎症和血栓形成等多种病理生理起始过程,是血栓形成的重要介质和靶分子.检验P.选择素可以通过流式细胞仪检测血小板表面的P一选择素或通过酶联免疫吸附试验检测血液中可溶性P-选择素,方法简便,这些数据可作为血小板激活的判断.从而为血栓形成提供依据.抑制P一选择素及其配体的结合,可使病理状态下血栓局部白细胞聚集减少,细胞因子及组织因子表达降低,纤维蛋白生成减少,从而有助于抑制血栓的形成.     

黏附分子细胞间黏附分子-1/E-选择素与冠心病

冠心病是一种高发病率和高病死率的疾病,炎症反应在冠状动脉粥样硬化斑块的形成中起着重要作用。活化的血管内皮细胞分泌的细胞黏附分子,如细胞间黏附分子-1和E-选择素等,它们介导内皮细胞与白细胞、血小板间的起始黏附,促进血液循环中白细胞、血小板黏附于血管内皮,引起炎症反应、血栓形成等,在动脉粥样硬化和冠心病的发生、发展中起重要作用。     

sP-选择素和P-选择素的研究进展及临床应用

P-选择素是主要表达于血小板和内皮细胞上的黏附分子,sP-选择素是其可溶性状态,通过与配体的结合,引起血小板、内皮细胞和白细胞的相互连接和生理功能的改变.近年来众多学者从对P-选择素的基本分子结构、生理功能和临床上与多种疾病的相关性等方面的研究取得较大的进展与突破.文章就sP-选择素研究进展和临床上的应用作一综述.     

P-选择素与缺血性脑损伤

P-选择素为黏附分子选择素家族的主要成员,是一种存在于血小板α颗粒和血管内皮细胞Weibel-Palade小体的颗粒膜蛋白。当内皮细胞或血小板受到刺激时,P-选择素迅速表达于细胞表面,在缺血性脑损伤、血栓形成和炎症反应中起重要作用。文章介绍了P-选择素的生物学特性和在缺血性脑损伤中的作用。     

选择素与大肠癌转移的关系

肿瘤转移是一个多步骤、多环节、多因素参与的复杂过程,是肿瘤致死的主要原因。肿瘤侵袭转移过程中存在黏附分子及其介导的行为的改变。黏附分子是由细胞产生,存在于细胞表面,介导细胞与细胞间或细胞与基质问相互接触和结合的一类分子。选择素（Selectin）是细胞黏附分子中的一个家族,包括L-选择素、E-选择素和P-选择素,在肿瘤转移、炎症反应、血栓形成及其他疾病中起重要作用。     

E-选择素介导的炎症反应与冠状动脉内支架术后再狭窄

再狭窄是限制冠状动脉内支架术远期成功的重要因素。它是一个由内皮损伤触发的多种因子参与的损伤修复过程,主要包括：机械损伤内皮处非阻塞性血栓形成、新生内膜增生及血管重构等反应。E-选择素仅表达于活化的内皮细胞表面,主要作用是在炎症发生时介导白细胞与血管内皮细胞的起始黏附,以及介导白细胞之间、白细胞与血小板之间的黏附形成血栓,从而对支架置入后损伤的内膜增生过程产生影响。E-选择素的研究对揭示再狭窄发生机制及寻找新的治疗途径均具有重要意义。     

针刺对大鼠脑缺血再灌注模型白细胞浸润及E-选择素mRNA和蛋白表达的调节

目的探讨针刺抗脑缺血再灌注(I/R)炎性损伤的机制。方法采用线栓法制作大鼠大脑中动脉缺血模型(MCAO),进行HE染色、白细胞髓过氧化物酶(MPO)活性、E-选择素mRNA和蛋白表达的测定。结果再灌注3h各实验组MPO活性均增加,24~48h达到峰值,白细胞浸润最普遍。E-选择素mRNA和蛋白表达均发生于脑I/R后3h,分别于12和24h达到高峰(组内比较,P<0.01)。针刺可显著降低MPO活性及E-选择素mRNA和蛋白表达(与模型组比较,P<0.01),明显减轻白细胞浸润。结论早期针刺治疗可能通过下调E-选择素mRNA和蛋白的表达,抑制黏附分子介导的内皮细胞与中性白细胞的黏附浸润,以防治脑I/R炎性损伤。     

Increased expression of selectins in kidneys of patients with diabetic nephropathy

Summary In diabetic nephropathy leukocytes, mainly composed of monocytes/macrophages, which accumulate in the glomeruli and the interstitium, play an important part in the progression of glomerulosclerosis. The infiltration of leukocytes into inflammatory tissues or atherosclerotic lesions is mediated by adhesion molecules, which are expressed on the vascular endothelial cells, although little is known about the mechanism of leukocyte infiltration into diabetic renal tissues. P- and E-selectin are leukocyte adhesion molecules, which are expressed on the vascular endothelial cells and promote the adhesion of leukocytes to the endothelium. We investigated the expression of P- and E-selectin in the kidney tissue of patients with diabetic nephropathy and compared it with that of patients with other glomerular diseases (minimal change nephrotic syndrome, membranous nephropathy, IgA nephropathy, mesangioproliferative glomerulonephritis, and lupus nephritis). Expression of P- and E-selectin were both significantly increased in the glomeruli and the interstitium of patients with diabetic nephropathy as compared with those with other glomerular diseases. P- and E-selectin were both expressed along the glomerular capillaries and the peritubular capillaries in the interstitium. Neither P- nor E-selectin were correlated with the number of infiltrated leukocytes in the glomeruli, however, interestingly the E-selectin expression on peritubular capillaries was correlated with the number of infiltrated CD14 positive cells in the interstitium. These results suggest that E-selectin may play a key role in leukocyte infiltration into the renal interstitium in patients with diabetic nephropathy. [Diabetologia (1998) 41: 185–192] Received: 22 April 1997 and in final revised form: 29 September 1997     

Regulation of adhesion molecule expression by human synovial microvascular endothelial cells in vitro

Objective. To examine the in vitro expression of E-selectin, P-selectin, intercellular adhesion molecule 1 (ICAM-1), ICAM-2, vascular cell adhesion molecule 1 (VCAM-1), and platelet–endothelial cell adhesion molecule 1 (PECAM-1) by synovial microvascular endothelial cells (SMEC) in comparison with microvascular neonatal foreskin endothelial cells (FSE) and macrovascular human umbilical vein endothelial cells (HUVE). Methods. Cultured endothelial cells were treated for 4 hours with medium alone or tumor necrosis factor α (TNF α). The expression of endothelial adhesion molecules was evaluated by flow cytometry, cell enzyme-linked immunosorbent assay, and Northern blot analysis. Results. SMEC continuously expressed E-selectin under basal culture conditions, whereas FSE and HUVE did not. TNF α treatment of rheumatoid arthritis (RA) SMEC resulted in sustained peak expression of E-selectin for up to 24 hours, which subsequently declined but remained elevated even at 72 hours. In contrast, peak E-selectin expression in FSE and HUVE occurred between 4 hours and 16 hours after TNF α treatment and then declined to near basal levels by 24–48 hours. SMEC expressed significantly higher levels of ICAM-1 compared with HUVE under basal culture conditions. There was no difference between SMEC, FSE, and HUVE in the expression of P-selectin, VCAM-1, ICAM-2, or PECAM-1. Northern blot analysis demonstrated that the levels of E-selectin expression by TNF α-stimulated endothelial cells correlated with their respective messenger RNA levels. Conclusion. Regulation of E-selectin and ICAM-1 expression in RA synovial endothelium is different from that in neonatal foreskin and human umbilical vein endothelium. The augmented expression of adhesion molecules in RA synovial endothelium may facilitate the recruitment of leukocytes to this site.     

Activation of vascular adhesion protein-1 on liver endothelium results in an NF-kappaB-dependent increase in lymphocyte adhesion

Vascular adhesion protein-1 (VAP-1) is an adhesion molecule and amine oxidase that is expressed at high levels in the human liver. It promotes leukocyte adhesion to the liver in vivo and drives lymphocyte transmigration across hepatic sinusoidal endothelial cells in vitro. We report that in addition to supporting leukocyte adhesion, provision of specific substrate to VAP-1 results in hepatic endothelial cell activation, which can be abrogated by treatment with the enzyme inhibitor semicarbazide. VAP-1-mediated activation was rapid; dependent upon nuclear factor-kappaB, phosphatidylinositol-3 kinase, and mitogen-activated protein kinase pathways; and led to upregulation of the adhesion molecules E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 and secretion of the chemokine CXCL8. This response resulted in enhanced lymphocyte adhesion, was restricted to hepatic endothelial cells that expressed VAP-1, and was not observed in human umbilical vein endothelial cells. Conclusion: We propose that as well as directly promoting adhesion via interactions with the as yet unknown ligand, binding of enzyme substrate to VAP-1 can indirectly promote inflammatory cell recruitment via upregulation of adhesion molecules and chemokines. This response is likely to be important for the recruitment of leukocytes to the liver and suggests that VAP-1 inhibitors have therapeutic potential for treating chronic inflammatory liver disease.     

Angiopoietin-1 reduces VEGF-stimulated leukocyte adhesion to endothelial cells by reducing ICAM-1, VCAM-1, and E-selectin expression

Vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang1) are potent vasculogenic and angiogenic factors that hold promise as a means to produce therapeutic vascularization and angiogenesis. However, VEGF also acts as a proinflammatory cytokine by inducing adhesion molecules that bind leukocytes to endothelial cells, an initial and essential step toward inflammation. In the present study, we used human umbilical vascular endothelial cells (HUVECs) to examine the effect of Ang1 on VEGF-induced expression of three adhesion molecules: intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. Interestingly, Ang1 suppressed VEGF-induced expression of these adhesion molecules. Furthermore, Ang1 reduced VEGF-induced leukocyte adhesion to HUVECs. These results demonstrate that Ang1 counteracts VEGF-induced inflammation by reducing VEGF-induced endothelial adhesiveness.     

Reduced plaque formation induced by rosiglitazone in an STZ-diabetes mouse model of atherosclerosis is associated with downregulation of adhesion molecules

Adhesion molecules have been implicated in the development and progression of cardiovascular disease, which is highly prevalent in people with diabetes. Adhesion molecules can mediate adhesion of leukocytes to the endothelium. Furthermore, P-selectin expressed on platelets is able to mediate the adhesion of leukocytes to platelets. In this study, we examine the in-vivo and in-vitro effects of rosiglitazone with particular emphasis on three important adhesion molecules (VCAM-1, ICAM-1 and P-selectin). In the aorta of STZ-diabetic apolipoprotein E-deficient (apoE KO) mice, rosiglitazone significantly reduced both total and arch plaque area. The mechanism for this appeared to be reduced macrophage infiltration into the atherosclerotic plaque which was also associated with reduced mRNA levels for VCAM-1, ICAM-1, MCP-1 and P-selectin in the aorta. In-vitro studies revealed reduced cell adhesion of monocytic cells (THP-1) to fibrinogen and endothelial cells (HUVEC) after incubation with rosiglitazone. Furthermore, the reduction in leukocyte adhesion also correlated with significant reductions in mRNA levels for VCAM-1, ICAM-1 and P-selectin indicating that reduced macrophage infiltration in atherosclerotic plaques may occur as a result of a direct effect of rosiglitazone on adhesion molecules in both monocytes and endothelial cells. Thus, we have shown that rosiglitazone appears to have direct anti-atherosclerotic effects in an animal model of diabetes-associated atherosclerosis which are at least partly due to effects on VCAM-1, ICAM-1, MCP-1 and P-selectin expression which leads to decreased leukocyte adhesion and macrophage infiltration.     

P-selectin induces the expression of tissue factor on monocytes.

P-selectin on activated platelets and stimulated endothelial cells mediates cell adhesion with monocytes and neutrophils. Since activated platelets induce tissue factor on mononuclear leukocytes, we examined the effect of P-selectin on the expression of tissue factor activity in monocytes. Purified P-selectin stimulated tissue factor expression on mononuclear leukocytes in a dose-dependent manner. Chinese hamster ovary (CHO) cells expressing P-selectin stimulated tissue factor procoagulant activity in purified monocytes, whereas untransfected CHO cells and CHO cells expressing E-selectin did not. Anti-P-selectin antibodies inhibited the effects of purified P-selectin and CHO cells expressing P-selectin on monocytes. Incubation of CHO cells expressing P-selectin with monocytes leads to the development of tissue factor mRNA in monocytes and to the expression of tissue factor antigen on the monocyte surface. These results indicate that P-selectin upregulates the expression of tissue factor on monocytes as well as mediates the binding of platelets and endothelial cells with monocytes and neutrophils. The binding of P-selectin to monocytes in the area of vascular injury may be a component of a mechanism that initiates thrombosis.     

Platelet-neutrophil-interactions: linking hemostasis and inflammation

Platelets are essential for primary hemostasis, but they also play an important pro-inflammatory role. Platelets normally circulate in a quiescent state. Upon activation, platelets can secrete and present various molecules, change their shape as well as the expression pattern of adhesion molecules. These changes are associated with the adhesion of platelets to leukocytes and the vessel wall. The interaction of platelets with neutrophils promotes the recruitment of neutrophils into inflammatory tissue and thus participates in host defense. This interaction of neutrophils with platelets is mainly mediated through P-selectin and beta(2) and beta(3) integrins (CD11b/CD18, CD41/CD61). Platelets can also interact with endothelial cells and monocytes. Adherent platelets promote the 'secondary capture' of neutrophils and other leukocytes. In addition, platelets secrete neutrophil and endothelial activators inducing production of inflammatory cytokines. Thus, platelets are important amplifiers of acute inflammation.