Fretland D J, Widomski D L, Anglin C P, Gaginella T S
Gastrointestinal Diseases Research, Searle Research and Development, Skokie, Illinois 60077.
Prostaglandins Leukot Essent Fatty Acids. 1991 Sep;44(1):61-5. doi: 10.1016/0952-3278(91)90146-v.
Granulocyte diapedesis in response to the generation of defined chemotaxins such as leukotriene B4 (LTB4), 12(R)-hydroxyeicosatetraenoic acid [12(R)-HETE], C5a, platelet activating factor and others is a hallmark of the inflammatory process that is thought to contribute to the tissue pathology seen in a number of diseases. 6-trans-LTB4 arises through the myeloperoxidase (MPO)-dependent metabolism of sulfidopeptide leukotrienes and through the action of 5-lipoxygenase on 12(R)-HETE. The intradermal (i.d.) injection of 6-trans-LTB4 induces a dose and time dependent influx of granulocytes into the guinea-pig (Hartley) dermis. When various doses of the LTB4 receptor antagonist and antiinflammatory agent, SC-41930 (7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-3,4-dihydro- 8-propyl-2H-1-benzopyran-2-carboxylic acid) given 30 min ahead of i.d. injection of 6-trans-LTB4 (10 micrograms/i.d. site), granulocyte infiltration, as assessed by dermal levels of the neutrophil marker enzyme MPO was inhibited with an ED50 value of 9.8 mg/kg in the guinea-pig. When various doses (10-25 micrograms) 6-trans-LTB4 were injected in the mouse (CD-1) dermis, there was a dose-related increase in granulocyte accumulation at 4 h. Furthermore when mice were pretreated (-30 min) with SC-41930 (1 mg/kg) orally, the trafficking of granulocytes was inhibited (p less than .01) as assessed by dermal MPO levels. SC-41930 orally inhibits 6-trans-LTB4-induced granulocyte accumulation in the guinea-pig more potently than against the response to 12(R)-HETE(ED50:13.4 mg/kg) but less potently than against LTB4 (ED50:0.6 mg/kg). These multiple activities may contribute to this compound's potential as an inflammatory agent.
粒细胞跨内皮迁移以响应特定趋化因子的产生，如白三烯B4（LTB4）、12（R）-羟基二十碳四烯酸[12（R）-HETE]、C5a、血小板活化因子等，是炎症过程的一个标志，被认为与多种疾病中所见的组织病理学有关。6-反式-LTB4通过硫肽白三烯的髓过氧化物酶（MPO）依赖性代谢以及5-脂氧合酶对12（R）-HETE的作用而产生。皮内（i.d.）注射6-反式-LTB4会诱导粒细胞以剂量和时间依赖性方式流入豚鼠（哈特利）真皮。当在皮内注射6-反式-LTB4（10微克/皮内注射部位）前30分钟给予不同剂量的LTB4受体拮抗剂和抗炎药SC-41930（7-[3-（4-乙酰基-3-甲氧基-2-丙基苯氧基）-丙氧基]-3,4-二氢-8-丙基-2H-1-苯并吡喃-2-羧酸）时，通过中性粒细胞标记酶MPO的真皮水平评估，粒细胞浸润受到抑制，在豚鼠中的ED50值为9.8毫克/千克。当在小鼠（CD-1）真皮中注射不同剂量（10 - 25微克）的6-反式-LTB4时，4小时时粒细胞积累呈剂量相关增加。此外，当小鼠口服SC-41930（1毫克/千克）预处理（-30分钟）时，通过真皮MPO水平评估，粒细胞的迁移受到抑制（p <.01）。口服SC-41930对豚鼠中6-反式-LTB4诱导的粒细胞积累的抑制作用比对12（R）-HETE反应的抑制作用更强（ED50：13.4毫克/千克），但比对LTB4反应的抑制作用弱（ED�0：0.6毫克/千克）。这些多种活性可能有助于该化合物作为炎症药物的潜力。
