Release of neutrophil elastase and its role in tissue injury in acute inflammation: effect of the elastase inhibitor, FR134043
Release of neutrophil elastase and its role in tissue injury in acute inflammation: effect of the elastase inhibitor, FR134043
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DOI：
10.1016/s0014-2999(99)00268-x
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发表时间：
1999-06-11
影响因子：
5
通讯作者：
Okuhara, M
中科院分区：
文献类型：
--
作者：
Fujie, K;Shinguh, Y;Okuhara, M
神经弹性蛋白酶降解细胞外基质成分，并参与几种炎症状态下的组织破坏。我们检测了FR 134043、FR 134043二钠、FR 134043三钠和FR 134043三钠对体外和体内活化中性粒细胞弹性蛋白酶活性的抑制作用。（Z，1 S，15 S，18 S，24 S，27 R，29 S，34 S，37 R）-29-苄基-21-亚乙基-27-羟基-15-异丁酰氨基-34-异丙基-31，37-二甲基-10，16，19，22，30，32，35，38-八氧代-36-氧杂-9，11，17，20，23，28，31，33-octatatracyclo [16.13.6.124，28.03，8]octatriconta-3，5，7-trien-5，6-diyl disulfate，一种具有广泛特异性的弹性蛋白酶抑制剂，阐明了中性粒细胞弹性蛋白酶在急性炎症发病机制中的作用。在培养的人中性粒细胞，佛波酯肉豆蔻酸酯乙酸酯（PMA）和钙离子载体增加弹性蛋白酶活性的上清液中，这是扩增共存的单核白细胞。甲酰基-蛋氨酸-亮氨酸-苯丙氨酸刺激弹性蛋白酶释放的存在下，而不是没有，单核白细胞。气管内注射脂多糖可使大鼠支气管肺泡灌洗液中弹性蛋白酶活性升高。这些弹性蛋白酶活性被FR 134043显著抑制。用FR 134043在大鼠中的肠内治疗也抑制由脂多糖诱导的酶，尽管最大抑制为52%。通过用FR 134043预处理显著抑制小鼠中由PMA局部应用引起的耳水肿（在1 mg/耳时抑制38%）。在大鼠角叉菜胶诱导的关节损伤中，血浆外渗到滑膜腔中被1 mg/膝的FR 134043部分且显著地抑制，而弹性蛋白酶特异性抑制剂没有显示出效果。这些结果表明，中性粒细胞弹性蛋白酶是部分参与组织损伤的急性炎症引起的刺激，但角叉菜胶诱导的通透性增高。
Neutrophil elastase degrades extracellular matrix components and is involved in tissue destruction in several inflammatory states. We examined the inhibition of the elastase activity derived from activated neutrophils in vitro and in vivo by FR134043, disodium(Z,1S,15S,18S,24S,27R,29S,34S,37R)-29-benzyl-21-ethylidene-27-hydroxy-15-isobutyrylamino-34-isopropyl-31,37-dimethyl-10,16,19,22,30,32,35,38-octaoxo-36-oxa-9,11,17,20,23,28,31,33-octaazatetracyclo[16.13.6.124,28.03,8]octatriconta-3,5,7-trien-5,6-diyl disulfate, an elastase inhibitor with broad specificity, and elucidated the role of neutrophil elastase in pathogenesis of acute inflammation. In a culture of human neutrophils, phorbol myristate acetate (PMA) and calcium ionophore increased elastase activity in the supernatants, which was amplified by co-existing mononuclear leukocytes. Formyl–Met–Leu–Phe stimulated elastase release in the presence of, not without, mononuclear leukocytes. Intratracheal injection of lipopolysaccharide elevated the elastase activity in bronchoalveolar lavage fluid of rats. These elastase activities were significantly inhibited by FR134043. Intratracheal treatment with FR134043 in rats also inhibited the enzyme induced by lipopolysaccharide, though the maximum inhibition was 52%. Ear edema elicited by topical application of PMA in mice was significantly suppressed by pretreatment with FR134043 (38% inhibition at 1 mg/ear). In carrageenan-induced joint injury in rats, plasma extravasation into the synovial cavity was partially and significantly inhibited by FR134043 at 1 mg/knee, while an elastase-specific inhibitor showed no effect. These results suggest that neutrophil elastase is partially involved in tissue damage in acute inflammation provoked by irritants, but not in carrageenan-induced hyperpermeability.