ICAM-1/LFA-1的表达和胃癌TNM分期关系的研究

为研究 ICAM-1、LFA-1在正常胃粘膜中及胃癌中的表达 ,并评价其表达与胃癌 TNM分期的关系 ,对正常胃粘膜组织 2 0例 ,胃癌组织 75例按 TNM分期分为 、 、 、 组 ,标本 SABC免疫组化染色后 ,对阳性结果进行了分析。结果显示 ,正常胃粘膜组中 ICAM-1表达率高于胃癌组 ( P<0 .0 5 ) ,L FA-1表达率两组间差别无显著性 ( P>0 .0 5 ) ;ICAM-1表达率 组为 71.4% ( 15 /2 1) , 组为 40 .9% ( 9/2 2 ) , 组为 17.6% ( 3 /2 2 ) , 组为 10 % ( 1/10 ) , 组与 组间、 组与 组间比较均有显著性差异 ( P<0 .0 5 )     

白细胞去除术辅助治疗高白细胞急性白血病

高白细胞白血病 (ＨＬＬ)是指外周血白细胞 >10 0× 10 9 Ｌ的急性白血病。临床上常伴有高粘滞血症 ,易发生颅内出血、弥散性血管内凝血、呼吸窘迫综合征等严重并发症 ,早期病死率高。我们采用ＭＣＳ+ 血细胞分离机 ,早期快速去除病人外周血异常增多的白细胞 ,辅助治疗ＨＬＬ ,取得满意疗效 ,现报告如下。1　资料与方法1.1　一般资料　自 2 0 0 0年 6月至 2 0 0 1年 10月共有高白细胞白血病 7例 ,男 1例 ,女 6例 ,年龄 16～ 39岁 ,平均 2 6岁。其中 ,急性髓系白血病 6例 ,慢粒急变 1例 ,急淋 1例。去除前白细胞中位数 35 5 .33(2 30～ 5 97)…     

高白细胞性急性白血病临床特征分析

急性白血病患者外周血白细胞计数〉100×10^9／L时,称为高白细胞性急性白血病（hyperleukocytic acute leukemia,HLAL）,发病率占急性白血病的5％-20％,是急性白血病中的高危类型。本文对我院收治的101例HLAL的临床特征进行了分析,为相关研究提供参考数据。     

急性早幼粒细胞白血病临床治疗观察

目的：研究ATRA（维甲酸）＋ATO（三氧化二砷）＋小剂量HHT（高三尖杉酯碱）治疗急性早幼粒细胞白血病（APL）的临床疗效。方法将20例APL患者分为研究组和对照组各10例,两组均进行诱导治疗和巩固治疗,研究组行ATRA＋ATO＋小剂量HHT治疗,行HA化疗,对照组行ATRA＋ATO＋DNR（柔红霉素）治疗,行DA化疗。比较两组疗效。结果研究组治疗费用（19209±4530）元及不良反应率60%均明显低于对照组（P＜0.05）,两组在治疗时间、细胞形态学CR及融合基因转阴率方面差异无统计学意义（P〉0.05）。结论 ATRA＋ATO＋小剂量HHT治疗APL临床疗效显著,且治疗费用低廉,不良反应少,是高效、安全、经济的治疗方法,值得重视。     

急性早幼粒细胞白血病血象分析及相关治疗

目的分析急性早幼粒细胞白血病(APL)的血象改变,并进行危险分组。方法经骨髓象确诊的APL患者48例,依据其WBC及Plt进行危险分组。结果低危组、中危组及高危组APL患者分别为10例、27例、11例(22.9%)。结论高危组约占1/4,需调整治疗方案。     

外周血LFA-1和ICAM-1在非小细胞肺癌中的临床意义及表达

目的：探讨非小细胞肺癌血清中LFA-1和ICAM-1的表达在肿瘤侵袭转移过程中的作用机制。方法：采用双抗体夹心ABC-ELISA法测定。结果：（1）非小细胞肺癌患者血清中LFA—1和ICAM-1的含量明显高于对照组;差异具有显著性（P〈0．01）;（2）非小细胞肺癌患者LFA-1和ICAM-1间存在正相关性（P〈0．05）。（3）肺癌的I＋N期与I＋Ⅱ期相比血清LFA-1、ICAM-1均有显著差异（P〈0．05）。（4）有淋巴结转移者血清LFA-1和1CAM-1含量较无淋巴结转移者增高,差异显著（P〈0．05）。结论：LFA-1 ICAM-1可能是反映肺癌侵袭转移潜能的一个有效生物学指标。     

血必净对ICAM-1及其配体LFA-1在大鼠急性坏死性胰腺炎中表达的影响及意义

目的 检测血必净注射液对细胞间粘附分子-1(intercellular adhesion molecule-1,ICAM-1)及其配体LFA-1在大鼠急性坏死性胰腺炎(acute necrotizing pancreatitis,ANP)合并多器官损伤模型中表达的影响,探讨血必净注射液在ANP合并多器官损伤中的作用及其机制.方法 采用胰管结扎和胰腺被膜下多位点注射5%牛磺胆酸钠的方法,制成SD大鼠ANP合并多器官损伤模型.于多个时相点应用免疫组织化学(LSAB法)检测ICAM-1在胰腺及肺组织中的表达;采用流式细胞术,检测LFA-1在血中中性粒细胞表面表达的变化;并观察血必净注射液对腹水的产生、血淀粉酶、胰腺和肺组织学改变的影响.结果 ICAM-l及其配体LFA-1在血必净注射液处理组中的表达多明显低于ANP组(P＜0.05或P＜0.01).血必净注射液处理组中的腹水量、肺组织白细胞的浸润程度及病损评分多明显低于ANP组(P＜0.05或P＜0.01).结论 血必净注射液可以抑制ICAM-1及其配体LFA-1在SD大鼠ANP合并多器官损伤模型中的表达,减轻肺组织损伤程度,减少腹水的产生,从而在ANP合并多器官损伤的病变发展过程中发挥一定的保护作用.     

Small molecule antagonists of the LFA-1/ICAM-1 interaction as potential therapeutic agents

The interaction between leukocyte function-associated antigen-1 (LFA-1), a member of β₂ integrin family, and intracellular adhesion molecule-1 (ICAM-1) plays a critical role in mediating cell adhesion, leukocyte transmigration and augmentation of T-cell receptor signalling. Small molecule antagonists of LFA-1/ICAM-1 represent a new therapeutic area for treatment of diseases such as psoriasis, rheumatoid arthritis and ischaemic reperfusion injury. The rapid development of this field is evidenced by the increasing numbers of patents filed and numbers of promising preclinical compounds which have emerged in recent years. Most patents claiming LFA-1/ICAM-1-mediated adhesion inhibitors between January 1999 and April 2001 concerned small molecule inhibitors. This review focuses on the novel composition of matter patents in the area of small molecule LFA-1/ICAM-1 interaction antagonists. The mechanism of action for some molecules that inhibit this set of protein-protein interaction will also be discussed.     

胰岛素治疗大鼠脑外伤后ICAM-1表达的实验研究

目的分析胰岛素对大鼠脑外伤后ICAM-1表达的影响。方法 96只大鼠随机分为假手术组、外伤组、外伤后胰岛素干预Ⅰ组（剂量为2.5u/kg）、外伤后胰岛素干预Ⅱ组（剂量为5.0u/kg）,每组24只。测定每组大鼠血糖、胰岛素含量及ICAM-1表达,观察不同剂量胰岛素对脑外伤后大鼠ICAM-1表达的影响。结果外伤组及胰岛素干预1,2组大鼠伤后6h即可见I-CAM-1在脑内表达上调,24h表达达到高峰,72h有所回落,7d进一步下降。血糖、胰岛素含量变化也有相同趋势。其中同时期外伤组ICAM-1表达最多,其余依次为胰岛素干预Ⅰ组、干预Ⅱ组。结论胰岛素发挥脑保护作用可能是通过抑制ICAM-1的表达而实现的,且保护作用与胰岛素的剂量有关。     

Mechanism of Binding and Internalization of ICAM-1-Derived Cyclic Peptides by LFA-1 on the Surface of T Cells: A Potential Method for Targeted Drug Delivery

Purpose. Peptides derived from the Domain 1 of the adhesion molecule ICAM-1_1-21 are being developed as targeting ligands for LFA-1 receptors expressed on activated T cells. This work aims to elucidate the binding and internalization of ICAM-1-derived cyclic peptides (cIBL, cIBC, and cIBR) to LFA-1. Methods. Ninety-six-well plates coated with soluble LFA-1 (sLFA-1) were used to characterize the binding of FITC-labeled peptide. An anti-CD11a antibody to the I-domain of LFA-1 was used to inhibit the binding of these peptides, which was quantified using a fluorescence plate reader. An unrelated FITC-labeled cyclic peptide was used as a negative control, and PE-labeled anti-CD11a antibodies (PE-R3.2 and PE-R7.1) were used as positive controls. Peptide binding to cell surface LFA-1 was visualized using colocalization of FITC-cIBR peptide and PE-labeled anti-CD18 antibody (LFA-1 -subunit) on SKW-3 T cells by fluorescent microscopy. Inhibition of ICAM-1 binding to LFA-1 by peptides was evaluated using a Biacore assay. Binding and internalization of FITC-labeled peptides were evaluated by flow cytometry and confocal microscopy at 4°C and 37°C. Results. These FITC-labeled cyclic peptides bind to sLFA-1 and can be blocked by an anti-CD11a antibody to the I-domain, suggesting that their binding site is on the I-domain of LFA-1. The FITC-cIBR peptide was localized with an anti-CD18 antibody on the surface of T cells, indicating that the FITC-cIBR peptide binds to LFA-1 on the cell surface. Flow cytometry and confocal microscopy demonstrated that FITC-labeled peptides were internalized in a temperature-dependent manner. Biacore analysis demonstrated that these peptides did not inhibit sICAM-1 from binding to immobilized sLFA-1. However, the binding properties of the soluble forms of LFA-1 and ICAM-1 may not correlate to their interaction at the cell surface. Conclusions. Cyclic ICAM-1-derived peptides (cIBL, cIBC, and cIBR) bind to the I-domain of LFA-1 and are internalized by LFA-1 receptors on the surface of T cells. Therefore, these peptides could be used to target and deliver drugs to the cytoplasmic domain of T cells.     

Discovery and Development of Potent LFA-1/ICAM-1 Antagonist SAR 1118 as an Ophthalmic Solution for Treating Dry Eye

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依达拉奉抑制缺血再灌注肾脏ICAM-1的表达

目的探讨依达拉奉对大鼠肾脏缺血再灌注后ICAM-1表达的影响。方法将24只雄性Wistar大鼠随机分为假手术组(S组)、缺血再灌注组(I组)、依达拉奉治疗组(E组),其中S组和E组大鼠均夹闭双侧肾蒂45 min、再灌注24 h制成肾缺血再灌注损伤动物模型。缺血前和再灌注即刻,E组经尾静脉给予依达拉奉3 mg/kg,S组和I组经尾静脉给予等量生理盐水。于再灌注24 h取左肾苏木精-伊红染色观察炎症细胞浸润情况,免疫组织化学观察ICAM-1表达。结果光镜下S组结构正常,I组中大量炎症细胞浸润肾间质,EB组炎症细胞浸润减少;免疫组织化学显示,I组中ICAM-1表达较S组上升,EB组则较I组下降(P<0.05)。结论依达拉奉抑制大鼠肾脏缺血再灌注损伤时ICAM-1的表达。     

NF-kappaB对ICAM-1表达的调节作用

目的:研究NF-kappaB对粘附分子ICAM-1表达的调控作用.方法:原代培养 HUVECs,用LPS(100 ng·ml-1)刺激不同时间(1、4、8、24 h)后,其中于4 h处预先用NF-κB抑制剂PDTC(1 mmol·L-1)处理15 min,再分别提取核蛋白进行凝胶电泳迁移改变分析(Electrophoretical Mobility Shift Assay EMSA)法测定NF-kappaB活性及提取总RNA进行RT-PCR检测ICAM-1mRNA表达.结果:NF-kappaB的活性变化与ICAM-1的表达有着明显的一致性.用PDTC(NF-kappaB抑制剂)处理内皮细胞,发现ICAM-1的表达随着NF-kappaB活性的降低而下调(2.40±0.11 vs 0.76±0.09,P<0.01).结论:NF-kappaB对ICAM-1基因表达起着重要的调控作用.     

Structural recognition of an ICAM-1 peptide by its receptor on the surface of T cells: conformational studies of cyclo (1, 12)-Pen-Pro-Arg-Gly-Gly-Ser-Val-Leu-Val-Thr-Gly-Cys-OH

Abstract: The purpose of this study is to elucidate the solution conformation of cyclic peptide 1 (cIBR), cyclo (1, 12)-Pen1-Pro2-Arg3-Gly4-Gly5-Ser6-Val7-Leu8-Val9-Thr10-Gly11-Cys12-OH, using NMR, circular dichroism (CD) and molecular dynamics (MD) simulation experiments. cIBR peptide ( 1 ), which is derived from the sequence of intercellular adhesion molecule-1 (ICAM-1, CD54), inhibits homotypic T-cell adhesion in vitro. The peptide hinders T-cell adhesion by inhibiting the leukocyte function-associated antigen-1 (LFA-1, CD11a/CD18) interaction with ICAM-1. Furthermore, Molt-3 T cells bind and internalize this peptide via cell surface receptors such as LFA-1. Peptide internalization by the LFA-1 receptor is one possible mechanism of inhibition of T-cell adhesion. The recognition of the peptide by LFA-1 is due to its sequence and conformation; therefore, this study can provide a better understanding for the conformational requirement of peptide–receptor interactions. The solution structure of 1 was determined using NMR, CD and MD simulation in aqueous solution. NMR showed a major and a minor conformer due to the presence of cis/trans isomerization at the X-Pro peptide bond. Because the contribution of the minor conformer is very small, this work is focused only on the major conformer. In solution, the major conformer shows a trans-configuration at the Pen1–Pro2 peptide bond as determined by HMQC NMR. The major conformer shows possible β-turns at Pro2-Arg3-Gly4-Gly5, Gly5-Ser6-Val7-Leu8, and Val9-Thr10-Gly11-Cys12. The first β-turn is supported by the ROE connectivities between the NH of Gly4 and the NH of Gly5. The connectivities between the NH of Ser6 and the NH of Val7, followed by the interaction between the amide protons of Val7 and Leu8, support the presence of the second β-turn. Furthermore, the presence of a β-turn at Val9-Thr10-Gly11-Cys12 is supported by the NH–NH connectivities between Thr10 and Gly11 and between Gly11 and Cys12. The propensity to form a type I β-turn structure is also supported by CD spectral analysis. The cIBR peptide ( 1 ) shows structural similarity at residues Pro2 to Val7 with the same sequence in the X-ray structure of D1-domain of ICAM-1. The conformation of Pro2 to Val7 in this peptide may be important for its binding selectivity to the LFA-1 receptor.     

大鼠局灶性脑缺血再灌注后不同时间E-选择素、P-选择素和细胞间粘附分子-1的表达

目的观察大鼠脑缺血再灌注(I/R)后不同时间P-选择素(P-selectin)、E-选择素(E-selectin)和细胞间粘附分子-1(ICAM-1)的表达及中性粒细胞浸润脑组织的情况,探讨粘附分子在脑缺血再灌注损伤中的作用。方法采用Zea-Longa线栓法,建立大鼠局灶性脑缺血模型。缺血1 h后拔出栓线进行再灌注,假手术组除不插线外其余手术操作同模型组。分别于再灌注后4、8、12、24、48 h,将动物麻醉下处死,快速取出脑组织,采用HE染色的方法,观察缺血再灌注不同时间脑组织形态学变化;采用免疫组化方法观察再灌注不同时间脑组织中P-selectin、E-selectin和ICAM-1的阳性表达数及表达部位;采用免疫荧光双标法,观察P-selectin、E-selectin和ICAM-1的表达及其定位;采用流式细胞术定量检测P-selectin、E-selectin和ICAM-1的表达;采用生化法测定缺血侧脑组织中髓过氧化物酶(MPO)的活性,以反映白细胞浸润的情况。结果缺血再灌注后,缺血侧脑组织发生明显的病理学形态改变,并且随着再灌注时间的延长,病理学形态改变逐渐加重。缺血再灌注后P-selectin、E-selectin、ICAM-1共表达于血管内皮细胞,与假手术组〔P-selectin:(4.99±0.08)channel;E-selectin:(4.17±0.13)channel;ICAM-1:(4.17±0.13)channel〕相比,I/R 4 h〔(5.46±0.09)channel;(4.60±0.14)channel;(4.56±0.12)chan-nel〕、I/R 8 h〔(5.87±0.24)channel;(5.08±0.14)chan-nel;(5.41±0.22)channel〕、I/R 12 h〔(6.48±0.18)chan-nel;(5.72±0.18)channel;(5.66±0.16)channel〕、I/R 24 h〔(7.16±0.11)channel;(6.09±0.09)channel;(5.61±0.09)channel〕及I/R 48 h〔(5.82±0.28)channel;(5.37±0.25)channel;(5.27±0.16)channel〕各组均升高(P<0.01),且表达峰值出现在缺血再灌注后24 h左右。在缺血再灌注后4~24 h大鼠脑组织中P-selectin(r=0.975,P<0.01)、E-selectin(r=0.977,P<0.01)和ICAM-1(r=0.749,P<0.01)的表达增加具有时间依赖性。脑缺血再灌注后MPO活性明显升高,I/R 4 h组(0.107±0.015)U.g-1、I/R8 h组(0.202±0.010)U.g-1、I/R 12 h组(0.242±0.010)U.g-1、I/R 24 h组(0.273±0.006)U.g-1和I/R 48h组(0.294±0.006)U.g-1与假手术组(0.043±0.008)U.g-1相比,差异均具有显著性(P<0.01),其峰值出现在缺血再灌注后48 h左右。在缺血再灌注后4~48 h,MPO活性增高具有时间依赖性(r=0.982,P<0.01)。结论大鼠局灶性脑缺血再灌注后24 h粘附分子E-selectin、P-selectin和ICAM-1表达增加最明显,而MPO活性在脑缺血再灌注后48h增加最明显,E-selectin、P-selectin和ICAM-1上调共同参与炎症反应,介导白细胞浸润,引起缺血再灌注性脑损伤。