选择性磷酸二酯酶3和4同工酶抑制剂及现有抗哮喘药物对炎性细胞活化的影响

The effect of selective phosphodiesterase 3 and 4 isoenzyme inhibitors and established anti-asthma drugs on inflammatory cell activation.

作者信息

Banner K H, Moriggi E, Da Ros B, Schioppacassi G, Semeraro C, Page C P

机构信息

Department of Pharmacology, King's College London.

出版信息

Br J Pharmacol. 1996 Nov;119(6):1255-61. doi: 10.1111/j.1476-5381.1996.tb16030.x.

DOI:10.1111/j.1476-5381.1996.tb16030.x

PMID:8937731

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1915886/

Abstract

This study aimed to evaluate the effects of phosphodiesterase (PDE) inhibitors and currently prescribed anti-asthma drugs for their ability to inhibit inflammatory cell activation in vitro. 2. Alveolar macrophages and eosinophils were isolated from the bronchoalveolar lavage (BAL) fluid of ovalbumin (Ovalb)-sensitized guinea-pigs. Opsonized zymosan (OZ) and PAF stimulated leukotriene B4 (LTB4) release from eosinophils was measured by radioimmunoassay. Ovalb-induced superoxide generation was measured by reduction of cytochrome C. 3. Monocytes were separated from human peripheral venous blood and mast cells were dispersed from human lung fragments. Lipopolysaccharide (LPS)-induced tumour necrosis factor-alpha (TNF-alpha) release from monocytes was measured by ELISA and anti-IgE stimulated histamine release from mast cells was measured by a radioenzymatic method. 4. The beta 2 agonist, salbutamol inhibited TNF-alpha release from monocytes and histamine release from mast cells whilst having no effect on eosinophil-derived LTB4 release or macrophage superoxide generation. 5. The PDE 3 inhibitor, milrinone produced a concentration-related inhibition of TNF-alpha release from monocytes which achieved statistical significance at 10(-5) M but inhibited LTB4 release from eosinophils and superoxide generation from macrophages only at the highest concentration (10(-3) M) examined. Milrinone had no effect on histamine release from mast cells. 6. The selective PDE 4 inhibitors, denbufylline and rolipram and the corticosteroid, beclomethasone produced a concentration-related inhibition of LTB4 release from eosinophils, TNF-alpha release from monocytes and superoxide generation from alveolar macrophages whilst having no effect on histamine release from mast cells. 7. The mixed PDE 3/4 inhibitor, benzafentrine produced a concentration-related inhibition of LTB4 release from eosinophils, TNF-alpha release from monocytes, superoxide generation from alveolar macrophages and histamine release from mast cells. 8. In conclusion these data clearly show that both established anti-asthma medication as well as PDE inhibitors have the potential to inhibit inflammatory cell activation in vitro but that the anti-secretory actions of beta 2 agonists, corticosteroids and PDE inhibitors are distinct.

摘要

本研究旨在评估磷酸二酯酶（PDE）抑制剂及目前常用的抗哮喘药物在体外抑制炎症细胞活化的能力。2. 从卵清蛋白（Ovalb）致敏豚鼠的支气管肺泡灌洗（BAL）液中分离出肺泡巨噬细胞和嗜酸性粒细胞。用放射免疫分析法测定经调理的酵母聚糖（OZ）和血小板活化因子（PAF）刺激嗜酸性粒细胞释放白三烯B4（LTB4）的情况。通过细胞色素C还原法测定Ovalb诱导的超氧化物生成。3. 从人外周静脉血中分离单核细胞，从人肺组织碎片中分离肥大细胞。用酶联免疫吸附测定法（ELISA）测定脂多糖（LPS）诱导单核细胞释放肿瘤坏死因子-α（TNF-α）的情况，用放射酶法测定抗IgE刺激肥大细胞释放组胺的情况。4. β2激动剂沙丁胺醇抑制单核细胞释放TNF-α和肥大细胞释放组胺，而对嗜酸性粒细胞源性LTB4释放或巨噬细胞超氧化物生成无影响。5. PDE 3抑制剂米力农对单核细胞释放TNF-α产生浓度相关的抑制作用，在10^(-5) M时具有统计学意义，但仅在最高检测浓度（10^(-3) M）时抑制嗜酸性粒细胞释放LTB4和巨噬细胞超氧化物生成。米力农对肥大细胞释放组胺无影响。6. 选择性PDE 4抑制剂登布茶碱和咯利普兰以及皮质类固醇倍氯米松对嗜酸性粒细胞释放LTB4、单核细胞释放TNF-α和肺泡巨噬细胞超氧化物生成产生浓度相关的抑制作用，但对肥大细胞释放组胺无影响。7. 混合PDE 3/4抑制剂苯扎芬特对嗜酸性粒细胞释放LTB4、单核细胞释放TNF-α、肺泡巨噬细胞超氧化物生成和肥大细胞释放组胺产生浓度相关的抑制作用。8. 总之，这些数据清楚地表明，既定的抗哮喘药物以及PDE抑制剂在体外均有抑制炎症细胞活化的潜力，但β2激动剂、皮质类固醇和PDE抑制剂的抗分泌作用各不相同。