Schick B, Austen K F
Immunology. 1985 Nov;56(3):513-22.
The action of pharmacologic agents on chymase-induced exocytosis of beta-hexosaminidase and arachidonic acid (AA) metabolism by rat serosal mast cells (RSMC) was determined and compared with their effects on anti-IgE induced activation. Indomethacin (INDO) (less than or equal to 10 microM), a cyclooxygenase inhibitor, did not affect chymase- or anti-IgE-mediated exocytosis, while completely inhibiting prostaglandin D2 (PGD2) release at 1.25 microM. Theophylline (THEO), mepacrine, 3-amino-1-[m-(trifluoromethyl)-phenyl]-2-pyrazoline (BW755C), and diethylcarbamazine (DEC), inhibitors of adenosine binding and phosphodiesterases, phospholipases, AA metabolism, and vesicular transport as well as leukotriene A4 formation, respectively, inhibited exocytosis with ID50 values of 3.4, 0.22, 3.4 and 1.9 mM for chymase and 2.4, 0.17, 2.8 and 5.2 mM for anti-IgE. These agents inhibited net PGD2 release with ID50 values of 2.1, 0.04, less than 0.05, and 1.5 mM for chymase and of 0.5, 0.1, less than 0.05, and 4 mM for anti-IgE. 5,6-Dehydroarachidonic acid (DHA) and arachidonyl hydroxylamine (AH), 5-lipoxygenase inhibitors, did not affect chymase-mediated exocytosis; anti-IgE-mediated exocytosis was not altered by AH but was suppressed by DHA (ID50 = 20 microM). Nordihydroguaiaretic acid (NDGA), an antioxidant, inhibited chymase-mediated exocytosis dose-dependently (ID50 less than or equal to 13.3 microM) while decreasing anti-IgE-mediated exocytosis by only 30% at 2.5-20 microM; net PGD2 release induced by both stimuli was inhibited dose-dependently. 2',5'-Dideoxyadenosine (DDA) and 1,6-di(0-(carbamoyl)cyclohexanone oxime)hexane (RHC 80267) and inhibitors of adenylate cyclase and of di-triglyceride lipases, respectively, had little effect on exocytosis induced by chymase but inhibited that induced by anti-IgE with ID50 values of 0.4 mM and 37 microM, respectively. With DDA the inhibition of net PGD2 release occurred with anti-IgE but not chymase, whereas RHC 80267 inhibited both chymase and anti-IgE-mediated PGD2 release. Differential inhibition of activation-secretion suggests either that chymase provides a step inhibited in IgE-mediated exocytosis by DDA, RHC 80267 and DHA, or that the activating pathway initiated by chymase is distinct.
测定了药理试剂对大鼠浆膜肥大细胞（RSMC）中糜酶诱导的β-己糖胺酶胞吐作用及花生四烯酸（AA）代谢的影响，并将其与它们对抗IgE诱导激活的作用进行了比较。环氧化酶抑制剂吲哚美辛（INDO）（≤10μM）不影响糜酶或抗IgE介导的胞吐作用，但在1.25μM时能完全抑制前列腺素D2（PGD2）的释放。茶碱（THEO）、米帕林、3-氨基-1-[间（三氟甲基）苯基]-2-吡唑啉（BW755C）和二乙氨基甲酰嗪（DEC）分别为腺苷结合和磷酸二酯酶、磷脂酶、AA代谢、囊泡运输以及白三烯A4形成的抑制剂，它们对糜酶介导的胞吐作用的半数抑制浓度（ID50）值分别为3.4、0.22、3.4和1.9 mM，对抗IgE介导的胞吐作用的ID50值分别为2.4、0.17、2.8和5.2 mM。这些试剂对糜酶介导的净PGD2释放的ID50值分别为2.1、0.04、＜0.05和1.5 mM，对抗IgE介导的净PGD2释放的ID50值分别为0.5、0.1、＜0.05和4 mM。5,6-脱氢花生四烯酸（DHA）和花生四烯酰羟胺（AH）作为5-脂氧合酶抑制剂，不影响糜酶介导的胞吐作用；AH不改变抗IgE介导的胞吐作用，但DHA可抑制该作用（ID50 = 20μM）。抗氧化剂去甲二氢愈创木酸（NDGA）剂量依赖性地抑制糜酶介导的胞吐作用（ID50≤13.3μM），而在2.5 - 20μM时仅使抗IgE介导的胞吐作用降低30%；两种刺激诱导的净PGD2释放均呈剂量依赖性抑制。2',5'-二脱氧腺苷（DDA）和1,6-二（0-（氨基甲酰基）环己酮肟）己烷（RHC 80267）分别为腺苷酸环化酶和二甘油三酯脂肪酶的抑制剂，它们对糜酶诱导的胞吐作用影响较小，但对抗IgE诱导的胞吐作用有抑制作用，ID50值分别为0.4 mM和37μM。对于DDA，抗IgE诱导的净PGD2释放受到抑制，而糜酶诱导的不受抑制，而RHC 80267抑制糜酶和抗IgE介导的PGD2释放。激活-分泌的差异抑制表明，要么糜酶提供了一个在DDA、RHC 80267和DHA介导的IgE介导的胞吐作用中被抑制的步骤，要么糜酶启动的激活途径是不同的。
