Adhesion molecules and atherogenesis

Atherosclerosis is an inflammatory disease of the vessel wall characterized by monocyte infiltration in response to pro‐atherogenic factors such as oxidized lipids. Recently, the role of specific adhesion molecules in this process has been explored. The endothelium overlying atherosclerotic lesions expresses P‐selectin and the shoulder regions express vascular cell adhesion molecule‐1 (VCAM‐1) and intercellular adhesion molecule‐1 (ICAM‐1), which is also expressed on endothelium in regions not prone to plaque development. Serum levels of soluble P‐selectin, ICAM‐1 and VCAM‐1 are elevated in patients with angina pectoris or peripheral atherosclerotic disease. Reconstituted in vitro systems using monocytes on cytokine‐activated endothelial cells under shear flow suggested the involvement of P‐selectin, L‐selectin, VCAM‐1, its ligand, VLA‐4 integrin and CD18 integrins. Studies of monocyte adhesion in isolated perfused carotid arteries harvested from atherosclerotic (apoE?/?) mice show a predominant involvement of P‐selectin and its ligand P‐selectin glycoprotein‐1 (PSGL‐1) in rolling and of VLA‐4 and VCAM‐1 in firm adhesion. Consistent with these findings, apoE?/? mice that are also deficient for P‐selectin show significantly reduced atherosclerotic lesion sizes and are almost completely protected from neointimal growth after vascular injury. Milder effects are also seen in the low‐density lipoprotein (LDL) receptor deficient (LDLR?/?) mouse. In a high cholesterol/cholate model, a role of ICAM‐1 and CD18 integrins was also shown, but this awaits confirmation in more physiologic models. Transient blockade of the VLA‐4/VCAM‐1 adhesion pathway by antibodies or peptides in apoE?/? or LDLR?/? mice reduced monocyte and lipid accumulation in lesions. These data suggest that P‐selectin, PSGL‐1, VLA‐4 and VCAM‐1 are the most important adhesion molecules involved in monocyte recruitment to atherosclerotic lesions.     

哮喘大鼠血清刺激下内皮细胞表面粘附分子ICAM—1的表达

近十五年人们才发现炎症是哮喘发病的病理基础,它以白细胞浸润为主要特征,过程由白细胞与内皮细胞表面粘附分子介导,ICAM－1就是其中之一,我们在前期活体动物实验中证实了哮喘动物肺组织中内皮细胞一白细胞粘附现象显著,并且肺组织ICAM－1高表达,这有可能是发病过程中ICAM－1大量表达于内皮细胞表面,导致内皮细胞一白细胞粘附增加的结果。本实验采用肺组织机械分离法体外培养大鼠肺内皮细胞,将哮喘病理血清与内皮细胞共同孵育,用于细胞粘附的体外研究,借助间接免疫荧光标记技术及流式细胞分离法,我们首先研究了受哮喘病理血清刺激后肺微血管内皮细胞表面ICAM－1表达的情况,结果发现,血清孵育的内皮细胞ICAM－1表达比用DMEM培养基培养的内皮细胞表达量高;哮喘血清刺激4h后ICAM－1表达量达到峰值,长于4h则很快降低;正常血清或培养基处理的内皮细胞表达持续在一个低水平。     

Expression of E-selectin, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 in non-small-cell lung carcinoma

Vascular cell adhesion molecules (VCAM) play an important part in the regulation of inflammation and are considered to be important in the process of malignant tumour growth. The present study describes the immunohistochemical staining patterns of E-selectin, intercellular adhesion molecule (ICAM)-1 and VCAM-1 on endothelial cells of the vessels in tumour stroma and other cell types in non-small-cell lung carcinoma (NSCLC; n=43) in association with inflammatory cells. Expression of E-selectin was dominant on endothelial cells in the stromal areas of the tumour, especially at the borders, and was confined to endothelial cells. Moderate to strong staining for ICAM-1 was demonstrated on endothelial cells irrespective of size or localization of the vessels. Compared with ICAM-1, fewer vessels were positive for VCAM-1, and stained with lesser intensity. ICAM-1 expression was demonstrated on NSCLC cells, the basal cells of bronchial epithelium, type II pneumocytes, lymphocytes and fibroblasts. VCAM-1 was clearly expressed on NSCLC cells in 4 of the 43 cases and on lymphocytes and fibroblasts. The staining patterns observed on endothelial cells support the idea of an active status of NSCLC vessels. This phenotypic pattern looks similar to the vascular component of inflammation. The presence of ICAM-1 and VCAM-1 on NSCLC cells suggests a functional role in the process of chemotaxis for tumour cells.     

β-1,4-半乳糖基转移酶6在淋巴细胞迁移中的分子机制研究

目的:研究β-1,4-半乳糖基转移酶6(β4galt6)在炎症条件下调节淋巴细胞迁移的分子机制。方法:CRISPR/Cas9敲除小鼠胰岛血管内皮细胞MS1上的β4galt6基因;黏附试验比较淋巴细胞与野生细胞株和基因敲除细胞株的黏附能力;RT-PCR及流式细胞术比较野生细胞株和基因敲除细胞株表面黏附分子的表达情况;Transwell模型比较淋巴细胞穿过野生细胞株和基因敲除细胞株的迁移能力。结果:基因敲除细胞株β4galt6 KO构建成功;淋巴细胞在炎症条件下与野生细胞株MS1的黏附显著高于与基因敲除细胞株β4galt6 KO;野生细胞株MS1表面细胞间黏附分子1(ICAM1)、血管内皮细胞黏附分子1(VCAM1)、P-selectin的表达显著高于基因敲除细胞株β4galt6 KO;淋巴细胞穿过野生细胞株MS1的能力显著高于基因敲除细胞株β4galt6 KO。结论:在炎症条件下,β4galt6能够促进淋巴细胞的迁移。     

Corticosterone treatment of pregnant low dose endotoxin-treated rats: inhibition of the inflammatory response

PROBLEM: Can the endotoxin‐induced inflammatory response, underlying experimental pre‐eclampsia, in pregnant rats be inhibited by corticosterone?
METHOD OF STUDY: On day 10 of pregnancy, rats were implanted with pellets containing 25% corticosterone and 75% cholesterol (n=10) or with 100% cholesterol‐pellets (n=10). On day 14 of pregnancy, rats were infused with either endotoxin (1.0 μg/kg bw) or saline. Three days later, they were sacrificed. Cryostat kidney sections were immunohistologically stained for the presence of neutrophils (PMN) and monocytes (M?) and the expression of inflammation‐associated adhesion molecules.
RESULTS: In cholesterol‐treated rats, endotoxin significantly increased glomerular numbers of PMN and M?, glomerular expression of ICAM‐1 and VCAM‐1 and glomerular numbers of LFA‐1 and VLA‐4‐positive cells as compared with saline. Corticosterone treatment significantly inhibited glomerular infiltration of PMN, M? and LFA‐1 positive cells after endotoxin infusion. It did not affect glomerular ICAM‐1 or VCAM‐1 expression or numbers of VLA‐4 positive cells.
CONCLUSIONS: It is concluded that pre‐treatment with corticosterone inhibits the low dose endotoxin‐induced glomerular inflammatory reaction in pregnant rats, most likely by inhibiting LFA‐1 expression, thereby decreasing the adhesiveness of inflammatory cells for activated endothelial cells.     

Immunohistochemical analysis of adhesion molecules in the micro-environment of portal tracts in relation to aberrant expression of PDC-E2 and HLA-DR on the bile ducts in primary biliary cirrhosis

We have examined immunohistochemically the expression of adhesion molecules in the micro-environment of portal tracts and their relationship to the expression of the pyruvate dehydrogenase E2 complex (PDC-E2) and HLA-DR in liver biopsy specimens. Ten cases of primary biliary cirrhosis (PBC) and 19 controls were examined, including four cases of extrahepatic biliary obstruction, six of chronic viral hepatitis, and nine normal livers. In PBC, the damaged small bile ducts demonstrated an increased expression of PDC-E2 and an aberrant expression of HLA-DR; about half of these damaged bile ducts also expressed intercellular adhesion molecules (ICAM)-1 and a few expressed vascular adhesion molecule (VCAM)-1. In addition, lymphocyte function-associated antigen (LFA)-1 and very late antigen (VLA)-4 were expressed on infiltrating lymphocytes around these bile ducts. In contrst, in control livers, these alterations in antigen expression on the bile ducts were either not observed or were only focal and weak, when present. These findings suggest that ICAM-1/LFA-1 and also VCAM-1/VLA-4 linkages between the damaged bile ducts and lymphocytes may facilitate antigen-specific reactions such as the presentation of antigens, possibly PDC-E2, to the periductal lymphocytes in PBC. ICAM-1, VCAM-1, and E-selectin were strongly expressed on the endothelial cells of some vessels in the portal tracts in PBC, suggesting the facilitation of the recruitment of lymphocytes around the of some vessels in the portal tracts in PBC, suggesting the facilitation of the recruitment of lymphocytes around the bile ducts of PBC. VCAM-1, a member of the immunoglobulin superfamily, has not hitherto been reported on bile ducts.     

Spatial distribution of cell adhesion molecules on the peritoneal surface in the cecal perforation‐induced peritonitis

For understanding the immunological functions of the peritoneum, spatial localization of integrins and their ligands was studied by immuno‐SEM on the peritoneal surface of mice with cecal perforation‐induced peritonitis. The cecal peritoneum 24 hr after perforation was stained with specific antibodies against LFA‐1, Mac‐1, VLA‐4, ICAM‐1, VCAM‐1, and fibronectin diluted with cold University of Wisconsin (UW) solution in conjunction with immuno‐gold labeling. The spatial localization of those cell adhesion molecules was detected by backscatter electron (BSE) imaging with field emission scanning electron microscope (FESEM). Numerous leukocytes with diverse surface ultrastructure were observed on the peritoneal surface by FESEM. Some leukocytes were in contact with mesothelial cells, and others adhered to the exposed underlying connective tissue. The BSE imaging showed the ubiquitous distribution of Mac‐1 on all membrane domains of leukocytes, i.e., cell body, ruffles, and microvilli. In contrast, predominant expressions of LFA‐1 and VLA‐4 were discernible on ruffles/microvilli of some leukocytes. The mesothelial cells remaining in the inflamed area expressed both ICAM‐1 and VCAM‐1 on their microvilli. The fibronectin was detected on presumable collagen fibers and/or fibrin over the exposed smooth muscle layer as well as on fibrin extending between leukocyte aggregation. The spatial microlocalization of integrins was clarified on the leukocytes emigrated in peritonitis, and their ligands were detected on the inflamed peritoneum. Anat Rec 264:219–227, 2001. © 2001 Wiley‐Liss, Inc.     

Role of Kaposi's sarcoma cells in recruitment of circulating leukocytes: implications in pathogenesis

OBJECTIVE: We sought to identify and characterize mechanisms of interaction between Kaposi's sarcoma cells and circulating leukocytes leading to leukocyte migration into the lesion. STUDY DESIGN/METHODS: By using static and dynamic adhesion models, we measured the ability of late-stage KSY1 cells to support adhesion and transmigration of peripheral blood lymphocytes (PBL). RESULTS: We showed that resting as well as TNF-alpha- or PMA-activated KSY1 cells supported adhesion and transmigration of PBL with a higher efficiency compared with normal endothelial cells. The LFA1/ICAM1 pathway was totally involved in PBL adhesion to resting or TNF-alpha-activated KSY1 cells and partially responsible for adhesion to PMA-activated KSY1 cells. No inhibition of adhesion was observed by blockage of the VLA4 pathway. Under flow conditions, PBL/KSY1 cell interaction was totally dependent on L-selectin. CONCLUSION: Our data indicate that KS cells mimic an endothelium-like structure by regulating extravasation of lymphocytes into lesions.     

Morphological aspects of LFA-1/ICAM-1 and VLA4/VCAM-1 adhesion pathways in human lymph nodes

Monoclonal antibodies specific for the adhesion molecules participating in lymphocyte homing, lymphocyte function associated antigen-1 (LFA-1) and very late antigen 4 (VLA4), and their respective ligands, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), were used to characterize their expression pattern in human lymph nodes by immunohistochemical and immunoelectron microscopic techniques. The location of LFA-1-positive lymphocytes and selective expression of ICAM-1 on the luminal plasma membrane of high endothelial venule endothelium suggested that the LFA-1/ICAM-1 adhesion pathway participates only in the initial step of the lymphocyte migration process. Lymphocytes passing through endothelium appear not to be influenced by this pathway. VCAM-1 was detected occasionally on the endothelium of high endothelial venules in the hyperplastic lymph nodes in the mesentery, but not in peripheral lymph nodes. VLA4-positive lymphocytes tended to be more frequently observed within high endothelial venules in mesenteric lymph nodes than in peripheral ones. Strong expression of both ligands, ICAM-1 and VCAM-1, was noted on the plasma membrane of follicular dendritic cells, and was especially prominent on their labyrinthine folding, and on the interdigitating cells in the paracortex. Furthermore, both LFA-1-and VLA4-positive lymphocytes localized around these cells. This suggests that LFA-1/ICAM-1 and VLA4/VCAM-1 adhesion pathways play an important role in the lymphocyte recognition of antigen-presenting cells.     

Glatiramer acetate attenuates the pro‐migratory profile of adhesion molecules on various immune cell subsets in multiple sclerosis

An altered expression pattern of adhesion molecules (AM) on the surface of immune cells is a premise for their extravasation into the central nervous system (CNS) and the formation of acute brain lesions in multiple sclerosis (MS). We evaluated the impact of glatiramer acetate (GA) on cell‐bound and soluble AM in the peripheral blood of patients with relapsing–remitting MS (RRMS). Fifteen patients treated de novo with GA were studied on four occasions over a period of 12 months. Surface levels of intracellular cell adhesion molecule (ICAM)‐1, ICAM‐3, lymphocyte function‐associated antigen (LFA)‐1 and very late activation antigen (VLA)‐4 were assessed in T cells (CD3⁺CD8⁺, CD3⁺CD4⁺), B cells, natural killer (NK) cells, natural killer T cells (NK T) and monocytes by five‐colour flow cytometry. Soluble E‐selectin, ICAM‐1, ICAM‐3, platelet endothelial cell adhesion molecule (PECAM)‐1, P‐selectin and vascular cell adhesion molecule (VCAM)‐1 were determined with a fluorescent bead‐based immunoassay. The pro‐migratory pattern in RRMS was verified by comparison with healthy controls and was characterized by up‐regulation of LFA‐1 (CD3⁺CD4⁺ T cells, B cells), VLA‐4 (CD3⁺CD8⁺ T cells, NK cells), ICAM‐1 (B cells) and ICAM‐3 (NK cells). Effects of GA treatment were most pronounced after 6 months and included attenuated levels of LFA‐1 (CD3⁺CD4⁺) and VLA‐4 (CD3⁺CD4⁺, CD3⁺CD8⁺, NK, NK T, monocytes). Further effects included lowering of ICAM‐1 and ICAM‐3 levels in almost all immune cell subsets. Soluble AM levels in RRMS did not differ from healthy controls and remained unaltered after GA treatment. The deregulated pro‐migratory expression profile of cell‐bound AM is altered by GA treatment. While this alteration may contribute to the beneficial action of the drug, the protracted development and unselective changes indicate more secondary immune regulatory phenomena related to these effects.     

终末糖基化产物对培养的人脐静脉内皮细胞粘附分子表达的影响

目的：探讨终末糖基化产物在糖尿病动脉粥样硬化（AS）形成中的作用机理。 方法： 分离正常人脐静脉内皮细胞（HUVECs），将终末糖基化终产物（AGE）修饰的人血清白蛋白（AGE-HSA）、人血清白蛋白（HSA）与HUVECs在体外共同培养，并用荧光单克隆抗体染色，流式细胞仪定量检测细胞间粘附分子-1（ICAM-1）、血管细胞粘附分子-1（VCAM-1）的表达。 结果： 正常人HUVEC表达ICAM-1和VCAM-1。AGE-HSA能以时间和剂量依赖的方式上调ICAM-1、VCAM-1的表达（P<0.05），而HSA对HUVECs上述粘附分子的表达均无影响。 结论： AGE能上调HUVECs粘附分子的表达，从而促进AS时单核/巨噬细胞的浸润。     

Developmental Changes of Cell Adhesion Molecule Expression in the Fetal Mouse Liver

Developmental changes of cell adhesion molecule expression, especially in nonparenchymal cells, have hardly ever been analyzed in the murine liver. The present study was undertaken to immunohistochemically examine the expression of NCAM, ICAM, VCAM, and N‐cadherin during mouse liver development and in fetal liver cell cultures. NCAM was transiently expressed in mesenchymal cells of the septum transversum and sinusoidal cells in liver development. In vitro studies demonstrated that desmin‐positive stellate cells expressed this cell adhesion molecule. NCAM expression in periportal biliary epithelial cells and connective tissue cells also coincided well with bile duct remodeling processes in the perinatal periods. Expression of ICAM and VCAM was transiently restricted to hepatoblasts, hepatocytes and hemopoietic cells in fetal stages. N‐cadherin was expressed not only in hepatoblasts and hepatocytes, but also in nonparenchymal cells such as endothelial cells, stellate cells and connective tissue cells, however the expression was weak. These results suggest that each cell adhesion molecule may play an important role during development in hepatic histogenesis, including hepatoblast/hepatocyte‐stellate cell interactions, hemopoiesis, and bile duct morphogenesis. Anat Rec 293:1698–1710, 2010. © 2010 Wiley‐Liss, Inc.     

OX-LDL诱导内皮细胞条件培养液对内皮细胞VCAM-1和ICAM-1的影响

目的探讨受损内皮细胞的自分泌和旁分泌对内皮细胞自身的影响。方法利用正常内皮细胞条件培养液和用氧化型低密度脂蛋白(OX-LDL)诱导内皮细胞的条件培养液分别作用于正常内皮细胞和受损内皮细胞,用酶联免疫细胞化学法检测血管内皮细胞黏附分子-1(VCAM-1)和细胞间黏附分子-1(ICAM-1)表达的变化。结果正常内皮细胞的条件培养液和OX-LDL诱导的内皮细胞条件培养液对正常内皮细胞VCAM-1和ICAM-1的表达作用不明显(P>0.05),而对受损内皮细胞VCAM-1和ICAM-1的表达具有明显的下调作用(P<0.01)。结论正常和受到氧化损伤的内皮细胞的自分泌和旁分泌作用对正常内皮细胞黏附分子没有影响,而对受损内皮细胞黏附分子有下调作用,说明内皮细胞可通过下调黏附分子的表达来实现自身的抗损伤作用。     

Levels of soluble adhesion molecules among normal and hypertensive type 2 diabetic patients

BACKGROUND: Hypertension and type-2 diabetes affect endothelial function, which in turn increases the expression of soluble adhesion molecules and lead to the development of vascular damage. The aim of this study was to assess soluble adhesion molecule levels among normotensive and hypertensive diabetic patients. MATERIAL AND METHODS: Serum levels of soluble VCAM1, ICAM1 and e-selectin were measured in 80 type-2 diabetic patients, (40 normotensive and 40 hypertensive), and in 40 normotensive non-diabetic subjects by ELISA (RyDSystems Minneapolis). Statistical analysis was performed with ANOVA. RESULTS: Among diabetic patients, levels of all three soluble adhesion molecules were significantly increased when compared with non-diabetic patients (p < 0.001 for all three molecules), In diabetic hypertensive patients, higher levels of ICAM1 were detected in comparison to normotensive diabetic patients (316 vs. 295 ng/ml p < 0.01), VCAM1 and e-selectin levels were not different between diabetic patients with and without hypertension. CONCLUSIONS: Diabetes is associated with increased levels of soluble adhesion molecules, suggesting a role of these molecules may play in endothelial damage. ICAM1 is further increased when hypertension and diabetes are present. The latter may explain why diabetic-hypertensive patients displayed more complications than normotensive patients.     

The use of the soluble adhesion molecules sE‐selectin,sICAM‐1, sVCAM‐1, sPECAM‐1 and their ligands CD11a and CD49d as diagnostic and prognostic biomarkers in septic and critically ill non‐septic ICU patients

Endothelial activation is pivotal in the development and escalation of sepsis. Central to endothelial activation is the endothelial up‐regulation of cellular adhesion molecules (CAMs) including E‐selectin, ICAM‐1, VCAM‐1, and PECAM‐1. Shed CAMs are also found in circulating soluble forms (sCAMs). We investigated whether sCAMs can be used as biomarkers for the differentiation between septic and non‐septic patients. Furthermore, we investigated lymphocyte and monocyte expression of LFA‐1 (CD11a/CD18) and VLA‐4 (CD49d/CD29) ligands for ICAM‐1 and VCAM‐1, respectively. Twenty‐one septic and 15 critically ill non‐septic patients were included. All patients had an APACHE II score above 13 at ICU admission. Fifteen healthy volunteers served as controls. Flow cytometry was used to estimate levels of sE‐selectin, sICAM‐1, sVCAM‐1, sPECAM‐1, and the cellular expression of CD11a and CD49d. Levels of sE‐selectin, sICAM‐1 and sPECAM‐1 were higher in the septic patients compared with the non‐septic patients and controls at admission and during the observation period. Lymphocyte and monocyte expression of CD11a and CD49d was suppressed or unaltered in the septic patients compared with the non‐septic patients and controls. Levels of sE‐selectin, sICAM‐1, and sPECAM‐1 were able to discriminate between septic and non‐septic patients, indicating that sCAMs may be potential diagnostic biomarkers of sepsis.     

Urokinase-type plasminogen activator modulates airway eosinophil adhesion in asthma

Eosinophils migrate from the vascular circulation to the inflamed airways during asthma exacerbations. While the mechanism(s) of this process is not known, the expression of urokinase-type plasminogen activator receptor (uPAR) has been found to modulate neutrophil adhesion and migration to inflammatory sites. We hypothesized that increased expression of uPAR and its ligand, uPA, enhance eosinophil adhesion in patients with asthma. Patients with allergic asthma underwent segmental bronchoprovocation with allergen; 48 h later, peripheral blood and airway (from bronchoalveolar lavage fluid) eosinophils were isolated. uPA and uPAR protein expression were measured by flow cytometry and Western blot; mRNA was quantified by real-time PCR. Eosinophil adhesion to intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 was assessed by eosinophil peroxidase activity. Airway eosinophils expressed significantly more uPA and uPAR protein and uPAR mRNA than peripheral blood eosinophils. Removal of cell-bound uPA and/or addition of exogenous uPA had no effect on blood eosinophil adhesion to ICAM-1 or VCAM-1. In contrast, exogenous uPA stimulated ICAM and VCAM adhesion of airway eosinophils. N-formyl-methionyl-leucyl-phenylalanine-activated airway eosinophil adherence to VCAM-1 and ICAM-1 (VCAM-1, 52.8 +/- 4.7%; ICAM-1, 49.2 +/- 5.3%) was increased over blood eosinophil adhesion (VCAM-1, 38.4 +/- 3.6%; ICAM-1, 27.7 +/- 4.9%; P < 0.05). Removal of cell-bound uPA from airway eosinophils decreased adhesion to blood cell levels; reintroduction of exogenous uPA completely restored adhesion levels. These data suggest that constitutive uPA primes, and exogenous uPA can activate, airway eosinophil adhesion following segmental allergen challenge and that increased uPA expression may be a mechanism of increased eosinophil infiltration and function in asthma.     

Disturbed homeostasis of lung intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 during sepsis

Cecal ligation and puncture (CLP)-induced sepsis in mice was associated with perturbations in vascular adhesion molecules. In CLP mice, lung vascular binding of (125)I-monoclonal antibodies to intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 revealed sharp increases in binding of anti-ICAM-1 and significantly reduced binding of anti-VCAM-1. In whole lung homogenates, intense ICAM-1 up-regulation was found (both in mRNA and in protein levels) during sepsis, whereas very little increase in VCAM-1 could be measured although some increased mRNA was found. During CLP soluble VCAM-1 (sVCAM-1) and soluble ICAM-1 (sICAM-1) appeared in the serum. When mouse dermal microvascular endothelial cells (MDMECs) were incubated with serum from CLP mice, constitutive endothelial VCAM-1 fell in association with the appearance of sVCAM-1 in the supernatant fluids. Under the same conditions, ICAM-1 cell content increased in MDMECs. When MDMECs were evaluated for leukocyte adhesion, exposure to CLP serum caused increased adhesion of neutrophils and decreased adhesion of macrophages and T cells. The progressive build-up in lung myeloperoxidase after CLP was ICAM-1-dependent and independent of VLA-4 and VCAM-1. These data suggest that sepsis disturbs endothelial homeostasis, greatly favoring neutrophil adhesion in the lung microvasculature, thereby putting the lung at increased risk of injury.     

Cigarette smoke extract induces expression of cell adhesion molecules in HUVEC via actin filament reorganization

Epidemiologic studies have shown a strong association between cigarette smoking and cardiovascular diseases. Various oxidative species and free radicals are produced during cigarette smoking and these lead to endothelial dysfunction and inflammation. Expression of adhesion molecules, such as intercellular adhesion molecule‐1 (ICAM‐1), E‐selectin, and vascular cell adhesion molecule‐1, and adhesion of leukocytes are present in atherosclerosis. We showed previously that a nonfractionated cigarette smoke extract (CSE) induces surface expression of ICAM‐1 and E‐selectin in human umbilical vein endothelial cells (HUVEC). We then investigated the role of the MAPKs (ERK1/2, JNK, and p38) and AP‐1 and the role of actin cytoskeleton reorganization in the CSE‐induced expression of ICAM‐1 and E‐selectin. Western blot analysis showed that CSE treatment rapidly and significantly caused phosphorylation of JNK and ERK1/2 but not of p38. Cytochalasin D (an actin filament disruptor) partially inhibited CSE‐induced ICAM‐1 and E‐selectin surface expression. However, inhibitors of ERK1/2 (PD98059) and JNK (SP600125) did not attenuate the CSE‐induced ICAM‐1 and E‐selectin surface expression. The results of electrophoretic mobility shift assay showed that CSE enhanced AP‐1 binding activity. Therefore, CSE activated AP‐1 and upregulated ICAM‐1 and E‐selectin surface expression in HUVEC seem to be via an MAPK‐independent pathway. Moreover, the dynamic reorganization of the actin cytoskeleton seems to be required for the CSE‐induced surface expression of ICAM‐1 and E‐selectin. Environ. Mol. Mutagen., 2009. © 2008 Wiley‐Liss, Inc.     

药物对C反应蛋白诱导脑微血管内皮细胞黏附分子表达的作用

目的探讨一些药物对C反应蛋白（CRP）诱导脑微血管内皮细胞黏附分子表达的作用，为缺血性脑损伤机制及防治策略的进一步研究提供理论依据。方法培养脑微血管内皮细胞（bEnd．3），经辛伐他汀、吡格列酮、Heroin和AG490预处理后与CRP共孵育，采用免疫蛋白印迹（Westernblot-ting）检测细胞黏附分子表达。结果CRP能显著诱导bEnd．3细胞表达细胞间黏附分子（ICAM-1）、血管细胞黏附分子（VCAM-1），信号转导子及转录激活子-3（STA33）酪氨酸残基快速磷酸化。辛伐他汀、吡格列酮和AG490均能显著减少ICAM-1、VCAM-1的表达。结论CRP上调黏附分子表达的作用可能与JAK／STAT信号转导通路有关。辛伐他汀、吡格列酮均能抑制CRP诱导的脑内皮细胞ICAM-1、VCAM-1表达，可能是它们对缺血性脑损伤的保护机制之一。