Effect of a single dose of the selectin inhibitor TBC1269 on early and late asthmatic responses

BACKGROUND : Selectins participate in the initial phase of leucocyte migration from circulation to inflamed tissues and may play a role in inflammatory cellular influx into airways in asthma. In the sheep asthma model, TBC1269, a pan-selectin antagonist, reduced late allergen response by 74%. OBJECTIVE : To determine whether a single dose of TBC1269 inhibits early (EAR) and late (LAR) asthmatic responses, and whether it inhibits sputum leucocyte influx after inhalation allergen challenge in atopic asthmatic subjects treated with bronchodilators only. METHODS : Twenty-one asthmatic subjects (mean+/-SD, age=32.5+/-6.7 years, 8 males, FEV1 percent predicted=84+/-15%) with known late asthmatic response based on a screening inhalation allergen challenge were randomly assigned to receive intravenous treatment with either placebo (n=11) or TBC1269 (n=10, 30 mg/kg) infused over 15 min immediately prior to a second (post-treatment) allergen challenge at least 4 weeks after the screening challenge. After each challenge, EAR and LAR were monitored for 7 h. In addition, sputum was induced 1 day before and 1 day after each allergen challenge. RESULTS : TBC1269 did not attenuate the EAR compared with placebo (largest fall in FEV1 within 1 h of 34.1+/-13.9% vs. 31.8+/-12.2% for TBC1269 and placebo groups respectively, P=0.61) or the LAR (largest fall in FEV1 between 3 and 7 h of 39.3+/-15.3% vs. 32.6+/-13.8%, P=0.24). TBC1269 had only minor effects on allergen-induced sputum eosinophilia. CONCLUSION : We conclude that TBC1269 administered before allergen challenge as a single intravenous dose does not attenuate early or late asthmatic responses to allergen in asthmatic subjects.     

L-选择蛋白在小鼠肝癌细胞高低转移株HCa-F、HCa-P的表达及与肿瘤转移潜能的相关性

目的　探讨经淋巴道转移的小鼠肝癌细胞高低转移株HCa F、HCa P淋巴道转移能力及与淋巴细胞归巢受体L 选择蛋白的相关性。方法　应用免疫印迹分析、RT PCR及流式细胞术检测小鼠肝癌HCa F、HCa P细胞表面L 选择蛋白的表达情况 ,再通过E 、P 、L 选择蛋白的抗体对细胞粘附实验的影响检测HCa F、HCa P细胞淋巴道转移潜能与L 选择蛋白的相关性。结果　L 选择蛋白在HCa F、HCa P细胞表面均有表达 ,且HCa F细胞的表达量明显高于HCa P细胞 (P <0 .0 1) ,HCa F细胞与淋巴结之间的粘附可被抗L 选择蛋白的抗体所阻断。结论　小鼠肝癌细胞高低转移株HCa F、HCa P细胞均表达L 选择蛋白 ,其程度与该细胞的淋巴道转移潜能正相关     

Endogenous glucocorticoids modulate experimental anti-glomerular basement membrane glomerulonephritis

The influence of endogenous glucocorticoids (GC) on glomerular injury was studied in a rat model of heterologous anti-glomerular basement membrane (GBM) glomerulonephritis (GN). Sprague-Dawley rats underwent adrenalectomy (ADX) or sham-operation 3 days prior to i.v. administration of both nephritogenic (100 microgram/g) and subnephritogenic (50 microgram/g) doses of sheep anti-rat GBM globulin. Administration of a subnephritogenic dose of anti-GBM globulin resulted in GN in adrenalectomized animals only. Similarly, ADX performed prior to administration of anti-GBM in the nephritogenic dose range resulted in exacerbation of GN compared with sham-operated animals (24 h protein excretion: 190.8 +/- 32.8 versus 42.5 +/- 2.6 mg/24 h; P < 0.005). In ADX animals receiving subnephritogenic doses of anti-GBM injury was manifested by abnormal proteinuria (62.7 +/- 5.8 mg/24 h), accumulation of neutrophils which peaked at 6 h (7.2 +/- 1.37 neutrophils per glomerular cross-section (neut/gcs)) and macrophage accumulation in glomeruli at 24 h (6.8 +/- 1.2 macrophages/gcs). Sham-adrenalectomized animals given the same dose of anti-GBM globulin developed minimal or no glomerular injury: urinary protein excretion (8.7 +/- 1.5 mg/24 h, P < 0.001); neutrophils (0.2 +/- 0.04 neutrophils/gcs, P < 0.001); macrophages (1.2 +/- 0.5 macrophages/gcs, P < 0.001). The increased cellular recruitment to glomeruli in adrenalectomized animals was associated with glomerular endothelial P-selectin expression. P-selectin expression was not detected in sham-operated rats after anti-GBM injection. Complement deposition in glomeruli was minimal in both groups. Physiologic GC replacement of ADX rats receiving subnephritogenic-dose anti-GBM reversed the observed susceptibility to GN development, with urinary protein excretion (7.8 +/- 1.12, P < 0.005) and no detectable P-selectin expression or leucocyte accumulation in glomeruli. These results suggest that endogenous GC modulate heterologous anti-GBM nephritis in rats and that this may be attributable, in part, to regulation of P-selectin expression.     

P-选择素启动子区C-2123G、T-1817C基因多态性的研究

目的研究P-选择素(P-selectin)基因启动子区C-2123G、T-1817C多态性在中国湖北地区健康汉族人群中的分布,同时比较不同种族间基因型及等位基因频率分布差异.方法应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)的分析方法,检测200名健康者P-selectin基因启动子区C-2123G、T-1817C的基因型并计算其基因型频率及等位基因频率.结果中国湖北地区健康人群P-selectin C-2123G基因各基因型频率:CC型8.0%,CG型40.5%,GG型51.5%;C,G各等位基因频率分别为28.2%,71.8%,这种基因多态性分布在男女间无显著性差异(P＞0.05).与德国和英国比较,发现不同种族间P-selectin C-2123G基因型分布及等位基因频率均存在显著差异(P＜0.001,P＜0.001).P-selectin T-1817C基因各基因型频率:TT型65.5%,TC型28.5%,CC型6.0%;T,C各等位频率分别为79.75%,20.25%,这种基因多态性分布在男女间无显著性差异(P＞0.05).与英国比较,发现不同种族间P-selectin T-2123基因型分布及等位基因频率均存在显著差异(P＜0.001).结论中国湖北地区汉族人群中存在P-selectin启动子区C-2123G、T-1817C基因多态性,这种多态性在同种族男女间无差异,在各族间存在着较大的差异.     

整合素血小板膜糖蛋白IIb、IIIa在系膜增殖性肾炎中的表达

目的 :观察整合素血小板膜糖蛋白Ⅱb、Ⅲa(GPⅡb、GPⅢa)在人类系膜增殖肾炎 (MsPGN)中肾内表达 ,探讨GPⅡb Ⅲa在MsPGN的作用。方法 :18例肾活检标本均行光镜HE、PAS、PASM Masson染色 ,电镜及免疫荧光检查 ,以SABC法测定肾组织中GPⅡb、GPⅢa、P 选择素 (P 140 )、纤维连接蛋白 (FN)、粘连蛋白 (LN)表达与正常对照组分别比较 ,并行计算机图像分析。结果 :PAS阳性物 (PAS+ )、PASM阳性物 (PASM+ )及FN、LN明显增生 ;GPⅡb、GPⅢa、P 140表达上调 ;肾小球细胞数 (n)、平均肾小球体积 (AVG)及肾小球硬化指数显著增加 ;肾小管、间质轻度受损。结论 :GPⅡb、GPⅢa在肾小球及肾小管间质表达上调与系膜细胞基质增生、细胞浸润、肾小球硬化相关 ;可能与肾小球疾病中凝血功能紊乱、血小板在肾脏的致病作用相关     

腮腺腺样囊性癌病人血浆P—选择素的测定

①目的　探讨可溶性P 选择素 (sP selectin)与腮腺腺样囊性癌发展及转移的关系。②方法　用ELISA法检测 6 5例腮腺腺样囊性癌病人血浆中sP selectin的含量。③结果　腮腺腺样囊性癌病人血浆中sP se lectin的含量均明显高于正常对照组 (t=- 12 .6 5 ,P <0 .0 1) ;而且血浆中sP selectin的水平与病情发展有关 (F =92 .6 7,q =5 .6 0 2～ 13.45 3,P <0 .0 1)。 ④结论　sP selectin检测有可能成为腮腺腺样囊性癌病人辅助诊断、观察病情发展的一项有价值的指标。     

慢性阻塞性肺疾病患者血清中细胞间粘附分子-1、E-选择素含量变化及意义

目的：研究细胞间粘附分子-1（ICAM-1）及E-选择素与慢性阻塞性肺疾病（COPD）发病的关系。方法：采用酶联免疫吸附试验（ELISA）方法检测30例DOPD急性加重期、缓解期的患者和20例正常对照者血清中的ICAM-1、E-选择素的水平,并将其与患者动脉血气中PO2、PCO2、肺功能FEV1%进行比较。结果：COPD患者中ICAM-1、E-选择素的水平明显高于正常对照组（P＜0.01),且急性加重期明显高于缓解期（P＜0.001),对19例急性加重期患者治疗前后对比分析具有显著差异（P＜0.001)。同时发现ICAM-1、E-选择素与PCO2呈正相关,与PO2及FEV1%呈负相关。结论：ICAM-1、E-选择素参与了COPD的发病,检测血清中的ICAM-1、E-选择素水平对判断COPD的病情轻重程度、治疗效果及预后具有重要的临床意义。     

血清可溶性E—选择素与2型糖尿病及其并发症相关性研究

目的　观察血清可溶性E 选择素在 2型糖尿病患者中的水平的变化 ,探讨E 选择素在糖尿病及其微血管并发症中的可能的作用机制。方法　应用酶联免疫吸附法 ,对 5 0例 2型糖尿病患者及 2 0名健康对照者进行了能够反映体内E 选择素表达水平的血清可溶性E 选择素水平的测定。结果　 (1)正常人血清可溶性E 选择素浓度为 41 7± 17 0ng/ml。与正常对照组比较 ,无大血管及微血管并发症的单纯糖尿病患者的血清可溶性E 选择素水平显著升高 (5 2 9± 2 3 0ng/ml,P <0 0 5 )。 (2 )合并糖尿病微血管病变的患者血清可溶性E 选择素浓度为6 7 3± 32 9ng/ml,高于单纯糖尿病患者 (P <0 0 5 )及正常对照 (P <0 0 1)。 (3)糖尿病患者血清E 选择素浓度与HbA1c水平呈正相关 (γ =0 31,P <0 0 1)。结论　血清可溶性E 选择素水平在 2型糖尿病及其微血管并发症中升高 ,并与代谢控制水平相关。E 选择素作为一种内皮细胞特异的粘附分子可能参与糖尿病及其微血管并发症的病理过程。