选择素及其信号转导

选择素家族是表达于白细胞、内皮细胞和血小板表面的粘附分子。免疫和炎症反应时 ,选择素与其配体结合介导白细胞同内皮细胞和血小板的粘附作用。此外 ,选择素还可启动细胞内信号转导通路 ,如可引起细胞内第二信使Ca2 的增加、MAPK及 β2 整合素的活化等 ,进一步调节细胞在粘附时的功能反应。     

缺血性脑血管疾病与粘附分子

实 验与临床研究已经证实脑缺血后的病理过程中有明显的炎性反应 ,目前主要研究与炎性细胞浸润有关的粘附分子和脑血管内皮方面。1　内皮细胞产生的粘附蛋白分子目前报道较多的是内皮细胞与白细胞之间相互作用的粘附分子 ,因为白细胞与内皮细胞的粘附并跨内皮细胞造成浸润等过程需要粘附分子的介导。内皮细胞产生的粘附分子主要有Ｅ ｓｅｌｅｃｔｉｎ(内皮选择素 ,主要存在于内皮细胞 )、Ｐ ｓｅｌｅｃｔｉｎ(血小板选择素 ,主要存在于内皮细胞及活化血小板内 )、ＩＣＡＭ 1(细胞间粘附分子 1)、ＶＣＡＭ 1(血管内皮细胞粘附分子 1)、ＰＥ…     

P-选择素与血栓性疾病

细胞黏附分子是介导细胞与细胞间,细胞与细胞外基质间相互接触和结合的一类分子,其通过受体-配体相互黏附作用而发挥生物学功能.黏附分子参与细胞的生长与分化、细胞间信号转导、血栓形成、创伤愈合、炎症免疫反应以及肿瘤浸润与转移等机体重要的病理生理过程[1～3].P-选择素是一类重要的细胞黏附分子,属选择素家族成员,主要表达在活化的血小板/内皮细胞表面,介导这些细胞间以及与白细胞的黏附,而有利于炎症部位白细胞招募到血栓部位[2～4],进而促进血栓的形成.本文就P-选择素及其在血栓形成中的作用作一简述.     

P—选择素与血小板活化

P 选择素介导白细胞与活化血小板和内皮细胞的粘附 ,促使细胞内一些活性物质的释放 ,造成血小板活化 ,导致血栓性疾病的形成。对P 选择素及其介导的血小板活化病理生理过程的深入研究 ,将为血栓性疾病的早期防治提供新思路和新方法     

选择素及其配体的研究进展

选择素是新发现的一类重要的黏附分子,主要介导炎症发生时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。选择素家族包括3个成员(L-选择素、P-选择素和E-选择素),它们的一个共同特点是N末端具有一个凝集素样的结构域。与选择素识别并相互作用的配体都是一些糖类化合物,包括糖蛋白、糖脂和蛋白聚糖。唾液酸化、岩藻糖化和硫酸化是这些配体的共同特征,对于配体的功能极为重要。     

P—选择素在心血管疾病中的研究进展

心血管疾病发生、发展涉及多种因素，其中血小板的活化及白细胞与内皮细胞之间的相互作用与心血管疾病关系尤为密切，近年来Ｐ－选择素在其中的作用日益引起关注。细胞及分子生物学水平的研究认为Ｐ－选择素与动脉粥样硬化、心肌梗塞、心肌缺血再灌注损伤等心血管疾病有密切关系，进一步阐明这些疾病发生的病理生理过程，可为临床诊断、防治心血管疾病寻找新的治疗途径提供理论依据。     

选择素及其配体的研究进展

选择素是新发现的一类重要的黏附分子，主要介导炎症发生时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。选择素家族包括3个成员（L-选择素、P-选择素和E-选择素），它们的一个共同特点是N末端具有一个凝集素样的结构域。与选择索识别并相互作用的配体都是一些糖类化合物，包括糖蛋白、糖脂和蛋白聚糖。唾液酸化、岩藻糖化和硫酸化是这些配体的共同特征，对于配体的功能极为重要。     

P-选择素在糖尿病中的研究进展

<正>细胞黏附分子选择素家族的重要成员P-选择素(P-selectin),储存于静止血小板的α颗粒和血管内皮细胞棒管状小体内。当血栓形成或炎症刺激致血小板活化时,其颗粒膜与胞质膜融合     

可溶性P-选择素在糖尿病患者血浆中的表达与临床意义

可溶性P-选择素（SP—sel）是一种糖蛋白，存在于血小板α颗粒和内皮细胞分泌颗粒内。SP—sel的受体主要存在于白细胞和内皮细胞表面。糖尿病时由于胰岛β细胞破坏，胰岛素分泌缺乏或作用缺陷或者两者同时存在而引起碳水化合物、蛋白质、脂肪代谢异常，导致多系统损害。为探讨SP-sel与糖尿病的关系，本文采用ELISA对159例糖尿病患者血浆SP-sel含量进行了检测，并探讨其临床意义。     

白细胞与内皮细胞,血小板粘附的分子机理及意义

白细胞与内皮细胞、血小板粘附的分子机理及意义中国协和医科大学药理室（北京１００００５）李福刚，汪钟各种血细胞与血管内皮细胞都有其独特的结构与功能，近年来随着生化、免疫、细胞生物学及分子生物学的开展，人们注意到在白细胞与内皮细胞、血小板间存在着复杂的相...     

Distinct Selectin Ligands on Colon Carcinoma Mucins Can Mediate Pathological Interactions among Platelets, Leukocytes, and Endothelium

Selectins are adhesion molecules that mediate calcium-dependent cell-cell interactions among leukocytes, platelets, and endothelial cells. The naturally occurring vascular ligands for the selectins are mostly mucin-type glycoproteins. Increased expression and altered glycosylation of mucins are known to be prominent features of carcinoma progression. We have previously shown that all three selectins bind to colon carcinoma cell lines in a calcium-dependent fashion and that carcinoma growth and metastasis formation are attenuated in P-selectin-deficient mice. Here we show that the three recombinant soluble selectins recognize ligands within primary colon carcinoma tissue samples. Affinity chromatography showed that the ligands for all three selectins are O-sialoglycoprotease-sensitive mucins that are recognized in a calcium- and sialic acid-dependent manner. Furthermore, there are separate binding sites on the mucins for each selectin, allowing cross-binding of a single mucin molecule by more than one selectin. We also show that the selectin ligands on purified carcinoma mucins can mediate at least four different pathological interactions among platelets, leukocytes, and endothelial cells. These findings could explain some of the adhesive events of blood-borne tumor cells reported to occur with leukocytes, platelets, and endothelial cells, which are believed to play a part in modulating some early events in tumor metastases.     

Selectins in normal pregnancy, pre-eclampsia and missed abortus

Selectins, are known to be increased in the serum of patients with pre-eclampsia, indicating that these molecules are possible markers of endothelial cell injury. In this study, we investigated P, E and L selectin levels in normal pregnancy, pre-eclampsia, and missed abortus. Plasma P and L selectins levels were significantly higher in normal pregnancy and pre-eclampsia than healthy controls; but plasma concentrations of E selectins were not different between these groups. Plasma P selectin was significantly higher in pre-eclampsia than normal pregnancy. Plasma concentrations of all selectins were significantly higher in missed abortus than healthy control. L selectin levels were higher in pre-eclampsia and missed abortus than normal pregnancy. We found the levels of selectins were increased in pre-eclampsia and missed abortus. Although selectins were suspected to play a role in the pathogenesis of pre-eclampsia, in conjunction with previous studies, we thought that elevated selectin levels are a non-specific consequence of endothelial injury rather than being a cause.     

Role of selectins in experimental Staphylococcus aureus-induced arthritis

The selectin family of adhesion molecules mediates the initial attachment of leukocytes to venular endothelial cells at sites of tissue injury and inflammation. To assess the role of selectin family in Staphylococcus aureus-triggered septic arthritis, we used several approaches. First, treatment with fucoidin, a carbohydrate molecule capable of binding to and blocking selectin functions, was used. In addition, we used P-selectin gene-targeted mice as well as mice pretreated with monoclonal antibody blocking L-selectin function. The P-selectin-deficient and fucoidin-treated animals initially exhibited a less severe septic arthritis both clinically and histopathologically. In the later stages of the disease no significant differences with respect to arthritis were evident. Pretreatment with L-selectin blocking antibody did not influence the severity of arthritis. High numbers of staphylococci were recovered from the kidneys of selectin-deficient mice, indicating a less efficient clearance of bacteria. Our results demonstrate a dual role for selectins in S. aureus-induced arthritis: on the one hand, blockade of these selectins leads to less severe arthritic lesions in the initial stage of the disease; on the other, delayed recruitment of phagocytes decreases the clearance of bacteria.     

Cell adhesion molecules in metastatic neuroblastoma models

Several cell adhesion molecules (CAMs) including selectins, integrins, cadherins and immunoglobulin-like CAMs are involved in leukocyte adhesion especially at sites of inflammation. In cancer cells, these CAMs have been associated with the growth and metastatic behavior in several malignant entities. In this study adhesion of LAN 1 and SK-N-SH neuroblastoma cells to selectins, hyaluronan and endothelial cells were determined under flow conditions. Furthermore cells were injected subcutaneously into wildtype and selectin deficient scid mice and their growth and metastatic behavior were analyzed. Under shear stress SK-N-SH cells firmly adhered to E-selectin-Fc-fusion protein, hyaluronan and endothelial cells, while LAN 1 cells showed less or hardly any adhesive events by comparison. In the SK-N-SH xenograft model metastasis formation was slightly dependent on the expression of selectins, while LAN 1 cells developed metastases completely independent of selectin expression. The different adhesive and metastatic properties of LAN 1 and SK-N-SH cells are reflected by a different expression profile of several CAMs. The results indicate that endothelial selectins are not essential for metastasis formation of human LAN 1 and SK-N-SH cells. However, other CAMs namely CD44, N-cadherin, NCAM and integrins were upregulated or downregulated, respectively, in SK-N-SH and LAN 1 cells and are potential adhesion molecules involved in the metastatic cascade of these cells.     

Intercellular cell adhesion molecule-1 and selectin ligands in acute cardiac allograft rejection: a study on gene-deficient mouse models

Cell adhesion molecules and their ligands are essential for regulating lymphocyte recirculation and leucocyte emigration into an inflamed or injured tissue. Vascular endothelial selectins as mediators of leucocyte rolling and intercellular cell adhesion molecule-1 (ICAM-1) have been found to be up-regulated on activated endothelium during acute allograft rejection. This study was designed to investigate whether ICAM-1 or selectin-ligand deficiency, or a combination of both, affected graft survival during acute cardiac allograft rejection. To this goal, we performed cardiac transplantation using mice deficient in genes for ICAM-1 or alpha(1,3)fucosyltransferase Fuc-TVII, representing a model for general absence of selectin-ligand expression, and a newly developed strain with a double mutation in Fuc-TVII and ICAM-1 alleles. Transplantation of a heart from ICAM-1 -/- or Fuc-TVII/ICAM-1 double-mutated mice into allogeneic recipients resulted in limited (2-2.5 days) but nevertheless significant prolongation of the graft survival (P<0.01 and P<0.01 in log-rank test) compared with the survival of unmodified hearts. When ICAM-1 -/- hearts were transplanted into Fuc-TVII -/- recipients, the median survival time was prolonged by 8 days (P<0.01). These data indicate that endothelial ICAM-1 is involved in adhesion events during acute cardiac allograft rejection but reveal that the loss of one type, selectin/leucocyte ligand or selectin/endothelial ligand interaction, does not markedly affect graft survival, thereby suggesting a role for other compensatory adhesion molecule/ligand interactions.     

The role of endothelial cell adhesion molecules P-selectin, E-selectin and intercellular adhesion molecule-1 in leucocyte recruitment induced by exogenous methylglyoxal

Methylglyoxal (MG) is a reactive dicarbonyl metabolite formed during glucose, protein and fatty acid metabolism. In hyperglycaemic conditions, increased MG level has been linked to the development of diabetes and its vascular complications at the macrovascular and microvascular levels where inflammation plays a role. To study the mechanism of MG‐induced inflammation in vivo, we applied MG locally to healthy mice and used intravital microscopy to investigate the role of endothelial cell adhesion molecules in MG‐induced leucocyte recruitment in cremasteric microvasculature. Administration of MG (25 and 50 mg/kg) to the tissue dose‐dependently induced leucocyte recruitment at 4·0–5·5 hr, with 84–92% recruited cells being neutrophils. Such MG treatment up‐regulated the expression of endothelial cell adhesion molecules P‐selectin, E‐selectin, intercellular adhesion molecule‐1, but not vascular cell adhesion molecule‐1. Activation of the nuclear factor‐κB signalling pathway contributed to MG‐induced up‐regulation of these adhesion molecules and leucocyte recruitment. The role of the up‐regulated endothelial cell adhesion molecules in MG‐induced leucocyte recruitment was determined by applying specific functional blocking antibodies to MG‐treated animals and observing changes in leucocyte recruitment parameters. Our data demonstrate that the up‐regulation of P‐selectin, E‐selectin and intercellular adhesion molecule‐1 contributes to the increased leucocyte rolling flux, reduced leucocyte rolling velocity, and increased leucocyte adhesion, respectively. Our results reveal the role of endothelial cell adhesion molecules in MG‐induced leucocyte recruitment in microvasculature, an inflammatory condition related to diabetic vascular complications.     

Over-sulfated glycosaminoglycans are alternative selectin ligands: insights into molecular interactions and possible role in breast cancer metastasis

Distant metastasis account for about 90 % of cancer associated deaths, and yet the oncology field is cruelly lacking tools to accurately predict and/or prevent metastasis. Distant metastasis occurs when circulating tumor cells interact with the endothelium of distant organs and extravasate from the blood vessel into the surrounding tissue. Selectins are a family of carbohydrate receptors well depicted for their role in tumor cells extravasation. They mediate primary interactions of cancer cells with endothelial cells, as well as secondary interactions with leucocytes and platelets, which are also promoting metastasis. The cancer associated carbohydrate antigen sialyl-Lewis x (sLe^x) has been repeatedly shown to be involved, as selectin ligand, in these interactions. However, recent studies have highlighted that glycosaminoglycans (GAGs), another class of glycans, may also serve as ligands for selectins. We report herein that cancer-associated GAGs are differentially recognized by selectins according to their density of sulfation and the pH conditions of the binding. We also show that these parameters regulate platelets-cancer cells heterotypic aggregation, supporting the idea that GAGs may have pro-metastatic function. Combining our experimental results with in depth analyses of molecular dockings, we propose a model of GAG/selectin interactions robust enough to recapitulate the differential binding of selectins to GAGs, the competition between GAGs and sLe^x for selectin binding and the effect of sub-physiological pH on GAGs affinities towards selectins. Altogether, our data suggest GAGs to be good ligands for selectins, potentially promoting distant metastasis in a complementary way to sLe^x.     

The involvement of the sLe-a selectin ligand in the extravasation of human colorectal carcinoma cells

The extravasation of tumor cells is a pivotal stage in the formation of hematogenous metastasis. An interaction of selectins expressed on endothelial cells and selectin ligands expressed by tumor cells has been implicated to play a role in extravasation. In the present study we used a human-mouse model to prove the hypothesis that the selectin ligand sialyl Lewis-a (sLe-a) is indeed involved in the in vivo extravasation of colorectal carcinoma (CRC) cells. The results indicated that highly metastatic CRC cells expressing high levels of sLe-a extravasate more efficiently than non-metastatic CRC cells expressing low levels of sLe-a. It was also demonstrated that down regulating the expression levels of sLe-a in CRC cells by genetic manipulations, significantly reduced CRC extravasation. Non-specific effects of these manipulations were ruled out. The results of this study indicate that the arrest and adhesion of CRC cells, and possibly of other types of cancer cells as well, to endothelium depend on the expression of the selectin ligand sLe-a by the tumor cells.     

Plasma soluble endothelial selectin is elevated in women with pre- eclampsia

The study was conducted to determine whether altered plasma concentrations of soluble selectins are involved in the pathogenesis of pre-eclampsia. Maternal plasma samples were collected from 20 patients with pre-eclampsia, and from 20 matched normotensive patients with uncomplicated pregnancies. Samples were assayed for soluble endothelial selectin (sES), platelet selectin (sPS) and leukocyte selectin (sLS) by specific enzyme-linked immunosorbent assay. The three soluble selectins were detectable in the plasma of all pre-eclamptic and control patients. The mean plasma concentrations of sPS and sLS were comparable between the groups. However, the mean plasma concentration of sES was significantly higher in the pre-eclamptic group compared with the control group (61 ng/ml +/- 30 ng/ml compared with 40 ng/ml +/- 17 ng/ml; P < 0.01). The selective increased plasma concentrations of sES in patients with pre-eclampsia provide specific evidence for endothelial activation and may reflect distinct pathways for neutrophil activation in pre-eclampsia.      

Development of synthetic pan-selectin antagonists: a new treatment strategy for chronic inflammation in asthma.

Asthma is characterized by chronic inflammation of large and small airways maintained by extravasation of leukocytes from the bloodstream into the surrounding peribronchial tissue. The process of extravasation is of crucial importance in inflammation and is mediated by a sequenced and concerted action between different adhesion molecules on endothelial cells and ligands on leukocytes. In this context, initial rolling and tethering is generally considered to be the primary event which is mediated by selectins, a family of glycoproteins comprised of E-, P- and L-selectin. Their role in asthma has been demonstrated in a variety of animal models, showing that all three selectins are involved in the chronic inflammation in asthma. Therefore, selectins are an attractive target where pan-selectin antagonism is the desired treatment strategy. Here, we give an overview of the status of the preclinical and clinical development of bimosiamose, the most advanced synthetic pan-selectin antagonist as a treatment for asthma.