慢性胃炎组织病理学变化与细胞间黏附分子-1表达的关系

目的研究慢性胃炎组织病理学变化与细胞间黏附分子-1（ICAM-1）的相关性。方法选择经胃镜和病理确诊为慢性胃炎的胃黏膜活检标本80例,幽门螺杆菌（Hp）的检测采用W-S银染法,ICAM-1的检测采用免疫组织化学方法。结果ICAM-1主要表达于胃黏膜间质内皮细胞及淋巴细胞表面,其表达随着Hp感染和慢性炎症的程度而增强;在黏膜萎缩、肠上皮化生和异型增生病例中,ICAM-1表达强阳性所占比例分别为45.6％、52.0％、47.4％。结论Hp感染促进胃黏膜组织ICAM-1高表达,其表达强度与慢性胃炎组织病理学变化程度呈正相关,ICAM-1在慢性胃炎发生发展过程中起重要作用。     

Fluvastatin and lovastatin inhibit granulocyte macrophage–colony stimulating factor‐stimulated human eosinophil adhesion to inter‐cellular adhesion molecule‐1 under flow conditions

Background Eosinophil accumulation in the lung is an important feature of airway inflammation in asthma. There is therefore much interest in developing novel therapies to prevent this process. Accumulating evidence suggests that statins have anti‐inflammatory properties, including inhibition of leucocyte accumulation. We therefore assessed the ability of five statins to inhibit human eosinophil adhesion to recombinant human inter‐cellular adhesion molecule (rhICAM)‐1 under physiologically relevant flow conditions. Methods Purified eosinophils were pre‐treated with a panel of statins before elucidation of the adhesion profiles of resting and granulocyte macrophage–colony stimulating factor (GM‐CSF)‐stimulated cells to rhICAM‐1‐coated microchannels at a flow rate of 0.5 dynes/cm². Images were recorded in real‐time at 1 min intervals and analysed using Ducocell software. Results Fluvastatin and lovastatin (both 10 nm ) significantly inhibited GM‐CSF‐stimulated eosinophil adhesion to rhICAM‐1 after 2 min (34.4±3.0% inhibition and 37.8±12.6% inhibition, respectively, n=4, P<0.05) but had no significant inhibitory effect on unstimulated eosinophil adhesion. Mevastatin, simvastatin, and pravastatin (all 10 nm ) had no significant effect on GM‐CSF‐stimulated eosinophil adhesion to rhICAM‐1. A concentration range of fluvastatin and lovastatin inhibited GM‐CSF stimulated eosinophil adhesion with significant (P<0.05) inhibition observed at low concentrations of 1 nm for both drugs. Mevalonate (100 nm ) reversed fluvastatin‐mediated but not lovastatin‐mediated inhibition of eosinophil adhesion. Conclusions Inhibition of eosinophil adhesion to ICAM‐1 by fluvastatin and lovastatin under physiological shear stress represent novel actions by these drugs that may inform the development of anti‐inflammatory therapy for allergic disease.     

肠癌淋巴管内皮细胞ICAM-1、CEA的表达

肠癌转移的主要途径是淋巴结转移。直接影响患者的预后。而淋巴系统转移首先是癌细胞沿着淋巴管转移 ,淋巴管转移涉及淋巴管内皮细胞与癌细胞的相互作用。这种相互作用的分子基础与细胞粘附分子有关。为此 ,本文运用石蜡切片免疫组化方法 ,研究 ICAM、CEA在淋巴管内皮细胞的表达 ,结果发现转移淋巴管内皮细胞表达 ICAM和 CEA,而正常淋巴管内皮细胞不表达 ICAM和 CEA,提示肠癌淋巴转移与淋巴管内皮细胞分泌 ICAM和 CEA有关     

大鼠皮脸移植后ICAM—1和LFA—1与排异反应的关系

目的 探讨细胞粘附分子和皮肤移植后排异反应之间的关系。方法 用HE及免疫组化方法观察20例大鼠Ⅲ度烫伤异体－自体皮肤混合移植和15例同种大鼠大张异体皮肤移植组织在移植后4－5，7，14，21和28d时细胞粘附分子ICAM－1和LFA－1的表达情况。结果 大鼠Ⅲ度烫伤后异体－自体皮肤混合移植组织中LFA－1^ 淋巴细胞和ICAM－1^ 细胞的表达均低于同种大张异体皮肤移植组织，与排异程度相一致，分别在移植后7和14d时差异显著（P＜0.05）。结论 ICAM－1／LFA－1不是主要促使皮肤混合移植排异反应中T细胞活化的共刺激信号，但ICAM－1^ 细胞和LFA－1^ 淋巴细胞在介导同种大张异体皮移植排异反应中起主要作用。     

A Separate Role for ICAM‐1 and Fluid Shear in Regulating Leukocyte Interactions with Straight Regions of Venular Wall and Venular Convergences

Objective: Variation in expression of adhesion molecules plays a key role in regulating leukocyte behavior, but the contribution of fluid shear to these interactions cannot be ignored. Here, we dissected the effects of each of these factors on leukocyte behavior in different venular regions. Materials and Methods: Leukocyte behavior was quantified in blood‐perfused microvascular networks in anesthetized mouse cremaster muscle, using intravital confocal microscopy. ICAM‐1 expression and fluid shear rate were quantified by using ICAM‐1 fluorescent labeling, fluorescent particle tracking, and computational fluid dynamics. Results: Tumor necrosis factor alpha induced an increase in ICAM‐1 expression and abolished the differences observed among control venules of different sizes. Consequently, leukocyte adhesion was increased to a similar level across all vessel sizes [5.1±0.46 leukocytes/100 μm vs. 2.1±0.47 (control)], but remained significantly higher in venular convergences (7.8±0.4). Leukocyte transmigration occurred primarily in the smallest venules and venular convergences (23.9±5.1 and 31.9±2.7 leukocytes/10,000 μm² tissue, respectively). In venular convergences, the two inlet vessels are predicted to create a region of low velocity, increasing leukocyte adhesion probability. Conclusions: In straight regions of different‐sized venules, the variability in ICAM‐1 expression accounts for the differences in leukocyte behavior; in converging regions, fluid shear potentially has a greater effect on leukocyte endothelial cell interactions.     

E-selectin 和ICAM-1反义寡核苷酸对内皮细胞黏附肝癌细胞的影响

目的：探讨反义寡核苷酸（ASODN）对内皮细胞表达Eselectin和ICAM1的抑制及黏附肝癌细胞的影响。方法： 应用ASODN转染内皮细胞，通过流式细胞技术测定TNFα诱导后内皮细胞膜Eselectin 和ICAM1的表达，RTPCR半定量测定Eselectin 和ICAM1 mRNA的表达，细胞黏附实验测定肝癌细胞与内皮细胞的黏附率。结果： 裸ASODN和脂质体ASODN均降低了内皮细胞Eselectin 和ICAM1分子及其mRNA的表达，后者尽管浓度低，作用更为明显；Eselectin的ASODN显著降低了内皮细胞黏附肝癌细胞的黏附率。结论： ASODN能竞争性地抑制内皮细胞黏附分子的表达，在一定程度上减少了肝癌细胞的黏附。     

Differential activation of astrocytes by innate and adaptive immune stimuli

The immunologic privilege of the central nervous system (CNS) makes it crucial that CNS resident cells be capable of responding rapidly to infection. Astrocytes have been reported to express Toll-like receptors (TLRs), hallmark pattern recognition receptors of the innate immune system, and respond to their ligation with cytokine production. Astrocytes have also been reported to respond to cytokines of the adaptive immune system with the induction of antigen presentation functions. Here we have compared the ability of TLR stimuli and the adaptive immune cytokines interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) to induce a variety of immunologic functions of astrocytes. We show that innate signals LPS- and poly I:C lead to stronger upregulation of TLRs and production of the cytokines IL-6 and TNF-alpha as well as innate immune effector molecules IFN-alpha4, IFN-beta, and iNOS compared with cytokine-stimulated astrocytes. Both innate stimulation and adaptive stimulation induce similar expression of the chemokines CCL2, CCL3, and CCL5, as well as similar enhancement of adhesion molecule ICAM-1 and VCAM-1 expression by astrocytes. Stimulation with adaptive immune cytokines, however, was unique in its ability to induce upregulation of MHC II and the functional ability of astrocytes to activate CD4(+) T cells. These results indicate potentially important and changing roles for astrocytes during the progression of CNS infection.     

Inhibition of LFA-1/ICAM-1 and VLA-4/VCAM-1 as a therapeutic approach to inflammation and autoimmune diseases

This review focuses on providing insights into the structural basis and clinical relevance of LFA-1 and VLA-4 inhibition by peptides and small molecules as adhesion-based therapeutic strategies for inflammation and autoimmune diseases. Interactions of cell adhesion molecules (CAM) play central roles in mediating immune and inflammatory responses. Leukocyte function-associated antigen (LFA-1, alpha(L)beta(2), and CD11a/CD18) and very late antigen (VLA-4, alpha(4)beta(1), and CD49d/CD29) are members of integrin-type CAM that are predominantly involved in leukocyte trafficking and extravasation. LFA-1 is exclusively expressed on leukocytes and interacts with its ligands ICAM-1, -2, and -3 to promote a variety of homotypic and heterotypic cell adhesion events required for normal and pathologic functions of the immune systems. VLA-4 is expressed mainly on lymphocyte, monocytes, and eosinophils, but is not found on neutrophils. VLA-4 interacts with its ligands VCAM-1 and fibronectin (FN) CS1 during chronic inflammatory diseases, such as rheumatoid arthritis, asthma, psoriasis, transplant-rejection, and allergy. Blockade of LFA-1 and VLA-4 interactions with their ligands is a potential target for immunosuppression. LFA-1 and VLA-4 antagonists (antibodies, peptides, and small molecules) are being developed for controlling inflammation and autoimmune diseases. The therapeutic intervention of mostly mAb-based has been extensively studied. However, due to the challenging relative efficacy/safety ratio of mAb-based therapy application, especially in terms of systemic administration and immunogenic potential, strategic alternatives in the forms of peptide, peptide mimetic inhibitors, and small molecule non-peptide antagonists are being sought. Linear and cyclic peptides derived from the sequences of LFA-1, ICAM-1, ICAM-2, VCAM-1, and FN C1 have been shown to have inhibitory effects in vitro and in vivo. Finally, understanding the mechanism of LFA-1 and VLA-4 binding to their ligands has become a fundamental basis in developing therapeutic agents for inflammation and autoimmune diseases.     

Neutrophils influence melanoma adhesion and migration under flow conditions

We have studied human melanoma cell (C8161) adhesion and migration in response to stimulation by soluble collagen IV (CIV) using a modified Boyden chamber. In this modified chamber, shear flow can be introduced over the cell-substrate interface, affecting tumor cell chemotactic migration through a microporous filter. A relatively high level of intercellular adhesion molecule-1 (ICAM-1) was found on C8161 cells. In contrast, levels of beta(2)-integrins (e.g., LFA-1 and Mac-1), the molecules that would be necessary for C8161 stable adhesion to the endothelium substrate, were found to be very low on these melanoma cells. As a result, C8161 transendothelial migration under a flow condition of 4 dyn/cm(2) decreased by 70% as compared to static migration. When human neutrophils (PMNs) were present in the tumor cell suspension, C8161 migration recovered by 85% over C8161 cells alone under the 4 dyn/cm(2) flow condition. Blocking ICAM-1 on C8161 cells or Mac-1 on PMNs significantly inhibited C8161-PMN adhesion and subsequent C8161 migration through the endothelium under flow conditions. In addition, increased interleukin-8 production and Mac-1 expression by PMNs were detected when they were co-cultured with C8161 melanoma cells. These results suggest that transmigration of C8161 cells under flow conditions can be influenced by PMNs, mediated by Mac-1/ICAM-1 adhesive interactions and enhanced by altered cytokine production.