Muramatsu M, Katada J, Hattori M, Hayashi I, Majima M
Department of Pharmacology, Kitasato University School of Medicine, 1-15-1 Kitasato Sagamihara-shi, Kanagawa 228-8555, Japan.
Eur J Pharmacol. 2000 Aug 18;402(1-2):181-91. doi: 10.1016/s0014-2999(00)00350-2.
We investigated the contribution of mast cell chymase in mast cell-dependent angiogenesis using the hamster sponge-implant model, where angiogenesis in the granulation tissue surrounding the subcutaneously implanted sponge was evaluated by measuring the hemoglobin content. Daily local injection of compound 48/80 (3-100 microg/site/day), a potent mast cell activator, induced formation of granulomas and angiogenesis in time- and dose-dependent manners. This angiogenic response was inhibited by chymase inhibitors including chymostatin (> or = 1 nmol/site/day), soybean trypsin inhibitor (SBTI; > or = 1.4 nmol/site/day) and lima bean trypsin inhibitor (LBTI; > or = 3.3 nmol/site/day), but not by a tryptase inhibitor like leupeptin (> or = 700 nmol/site/day). Although pyrilamine (> or = 2,580 nmol/site/day), a histamine H1 receptor antagonist, and protamine (300 microg/site/day) also inhibited angiogenesis, these effects were much less pronounced than those by chymase inhibitors. Furthermore, antigen-induced angiogenesis in hamsters pre-sensitized with ovalbumin was also inhibited by the chymase inhibitors by 60-70%. Our results suggest that chymase is a major mediator in mast cell-mediated angiogenesis.
我们使用仓鼠海绵植入模型研究了肥大细胞糜酶在肥大细胞依赖性血管生成中的作用，在该模型中，通过测量血红蛋白含量来评估皮下植入海绵周围肉芽组织中的血管生成。每天局部注射化合物48/80（3 - 100微克/部位/天），一种有效的肥大细胞激活剂，可诱导肉芽肿形成和血管生成，且呈时间和剂量依赖性。这种血管生成反应受到包括糜蛋白酶抑制素（≥1纳摩尔/部位/天）、大豆胰蛋白酶抑制剂（SBTI；≥1.4纳摩尔/部位/天）和利马豆胰蛋白酶抑制剂（LBTI；≥3.3纳摩尔/部位/天）在内的糜酶抑制剂的抑制，但不受像亮抑酶肽（≥700纳摩尔/部位/天）这样的类胰蛋白酶抑制剂的抑制。尽管组胺H1受体拮抗剂吡苄明（≥2580纳摩尔/部位/天）和鱼精蛋白（300微克/部位/天）也抑制血管生成，但这些作用远不如糜酶抑制剂明显。此外，用卵清蛋白预先致敏的仓鼠中抗原诱导的血管生成也被糜酶抑制剂抑制了60 - 70%。我们的结果表明，糜酶是肥大细胞介导的血管生成中的主要介质。
