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.     

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.     

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。     

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。     

大鼠输尿管梗阻后肾炎中的P-选择素表达及意义

目的　探讨粘附分子P-选择素在单侧输尿管梗阻后肾炎中的作用。方法　建立单侧输尿管梗阻(UUO)动物模型,观察肾组织病理改变和P-选择素在肾组织中的表达,以及抗P-选择素单克隆抗体(单抗)对其影响。结果　大鼠UUO第1d即见间质以单核巨噬细胞为主的炎细胞浸润和p-选择素在小管间质表达;第3d间质炎细胞增多,P-选择素明显表达;第7d间质炎细胞浸润达高峰伴间质水肿,而P-选择素表达下降。抗P-选择素单抗治疗组炎细胞浸润减轻,P-选择素表达减弱。结论　 P-选择素在UUO早期参与介导以单核巨噬细胞为主的炎细胞在肾间质浸润及肾间质损害,抗P-选择素单抗对此具有一定治疗作用。     

P选择素和ICAM—1在肾缺血再灌注损伤中的作用

目的 探讨Ｐ选择素和细胞间粘附分子－１（ＩＣＡＭ－１）在肾缺血再灌注损伤中的作用。方法 建立缺血再灌注损伤大鼠模型,观察缺血再灌注后肾组织Ｐ选择素和ＩＣＡＭ－１的表达,并用Ｐ选择单克隆抗体进行了治疗。结果 发现缺血再灌注后肾小管人泡变性玫片状坏死,血尿素氮（ＢＵＮ）和肌酐（ＳＣｒ）水平升高;但再灌注前５ｍｉｎ经Ｐ选择互单抗处理的动物肾组织与正常相近,肾小管上皮细胞未见变性及坏死,血ＢＵＮ和ＳＣｒ水     

穴位敷贴对哮喘豚鼠血清E、P选择素水平的影响

目的:探讨穴位敷贴治疗哮喘的机理。方法:将40只豚鼠随机分为正常对照组、哮喘模型组、穴位敷贴组、地塞米松组,每组10只。处理结束后采用酶联免疫吸附测定法检测血清E、P选择素水平。结果:模型组豚鼠血清E、P选择素水平明显高于正常对照组(P<0.01),穴位敷贴组和地塞米松组血清E、P选择素水平明显低于模型组(P<0.01)。结论:穴位敷贴可明显降低哮喘豚鼠血清E、P选择素的水平,这可能是其治疗哮喘的作用机理之一。     

Evidence of anti-inflammatory effects of Passiflora edulis in an inflammation model

The popular medicine Passiflora edulis has been used as a sedative, tranquilizer, against cutaneous inflammatory diseases and intermittent fever. Most of the pharmacological investigations of Passiflora edulis have been addressed to its Central Nervous System activities, such as anxiolytic, anticonvulsant and sedative actions. Otherwise, there are few reports about the anti-inflammatory activity of the Passiflora species. The aim of this study was to investigate the mechanism of the anti-inflammatory effect of aqueous lyophilized extract obtained from leaves of Passiflora edulis var. flavicarpa Degener (Passifloraceae) in the mouse model of pleurisy induced by carrageenan (Cg), bradykinin, histamine or substance P, observing the effects upon leucocytes migration, myeloperoxidase (MPO), nitric oxide (NO) concentrations and tumor necrosis factor-alpha (TNFalpha) and interleukin-1 beta (IL-1beta) levels. RESULTS: Passiflora edulis (250mg/kg) administered by intraperitoneal route (i.p.) inhibited the leukocyte, neutrophils, myeloperoxidase, nitric oxide, TNFalpha and IL-1beta levels (P<0.01) in the pleurisy induced by carrageenan. Passiflora edulis (250-500mg/kg, i.p.) also inhibited total and differential leukocytes in the pleurisy induced by bradykinin, histamine or substance P (P<0.05). CONCLUSION: Several mechanisms, including the inhibition of pro-inflammatory cytokines (TNFalpha, IL-1beta), enzyme (myeloperoxidase) and mediators (bradykinin, histamine, substance P, nitric oxide) release and/or action, appear to account for Passiflora edulis's actions.