“IV型”选择性磷酸二酯酶抑制剂对嗜酸性粒细胞环核苷酸磷酸二酯酶活性及调理酵母聚糖刺激的呼吸爆发的抑制作用

Inhibition of eosinophil cyclic nucleotide PDE activity and opsonised zymosan-stimulated respiratory burst by 'type IV'-selective PDE inhibitors.

Dent G, Giembycz M A, Rabe K F, Barnes P J

Department of Thoracic Medicine, National Heart and Lung Institute, London.

Br J Pharmacol. 1991 Jun;103(2):1339-46. doi: 10.1111/j.1476-5381.1991.tb09790.x.

Abstract

The cyclic nucleotide phosphodiesterase (PDE) of guinea-pig eosinophils was partially characterized and the effects of selective inhibitors of PDE isoenzymes upon opsonized zymosan (OZ)-stimulated respiratory burst were studied. 2. PDE activity in eosinophil lysates appeared to be membrane-associated, displayed substrate specificity for adenosine 3':5' cyclic monophosphate (cyclic AMP) versus guanosine 3':5' cyclic monophosphate (cyclic GMP) and was insensitive to cyclic GMP or Ca2+ and calmodulin. 3. The non-selective PDE inhibitor, 3-isobutyl-1-methylxanthine caused a concentration-dependent inhibition of both OZ-stimulated hydrogen peroxide (H2O2) generation and cyclic AMP hydrolysis. The type IV-selective PDE inhibitors, rolipram and denbufylline, also inhibited H2O2 generation and cyclic AMP hydrolysis in a concentration-dependent manner whilst SK&F 94120 and Org 9935 (type III-selective) and zaprinast (type Ia or V-selective) were ineffective. 4. Dibutyryl cyclic AMP, a cell-permeable, non-hydrolysable analogue of cyclic AMP, caused a concentration-dependent inhibition of H2O2 generation stimulated by OZ. Dibutyryl cyclic GMP was ineffective. 5. It is concluded that eosinophil respiratory burst activity induced by OZ can be regulated by intracellular cyclic AMP and that the levels of cyclic AMP are controlled exclusively by a rolipram- and denbufylline-sensitive PDE isoenzyme that resembles a type IV species.

摘要

对豚鼠嗜酸性粒细胞的环核苷酸磷酸二酯酶（PDE）进行了部分特性鉴定，并研究了PDE同工酶选择性抑制剂对调理酵母聚糖（OZ）刺激的呼吸爆发的影响。2. 嗜酸性粒细胞裂解物中的PDE活性似乎与膜相关，对腺苷3':5'环一磷酸（环磷酸腺苷，cAMP）与鸟苷3':5'环一磷酸（环磷酸鸟苷，cGMP）表现出底物特异性，且对cGMP、Ca2+和钙调蛋白不敏感。3. 非选择性PDE抑制剂3-异丁基-1-甲基黄嘌呤对OZ刺激的过氧化氢（H2O）生成和环磷酸腺苷水解均产生浓度依赖性抑制。IV型选择性PDE抑制剂咯利普兰和登布茶碱也以浓度依赖性方式抑制H2O生成和环磷酸腺苷水解，而SK&F 94120和Org 9935（III型选择性）以及扎普司特（Ia型或V型选择性）则无效。4. 二丁酰环磷酸腺苷是一种可透过细胞、不可水解的环磷酸腺苷类似物，对OZ刺激的H2O生成产生浓度依赖性抑制。二丁酰环磷酸鸟苷无效。5. 得出结论：OZ诱导的嗜酸性粒细胞呼吸爆发活性可由细胞内环磷酸腺苷调节，且环磷酸腺苷水平仅由一种对咯利普兰和登布茶碱敏感的PDE同工酶控制，该同工酶类似于IV型。