A potent tryptase inhibitor nafamostat mesilate dramatically suppressed pulmonary dysfunction induced in rats by a radiographic contrast medium
A potent tryptase inhibitor nafamostat mesilate dramatically suppressed pulmonary dysfunction induced in rats by a radiographic contrast medium
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一种有效的类胰蛋白酶抑制剂甲磺酸萘莫司他显着抑制放射造影剂诱导的大鼠肺功能障碍
DOI：
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发表时间：
2003
影响因子：
7.3
通讯作者：
R. Oishi
中科院分区：
文献类型：
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作者：
T. Sendo;Y. Itoh;Takeshi Goromaru;Tomoko Sumimura;Mami Saito;Keisei Aki;T. Yano;R. Oishi
静脉注射碘显影造影剂氧磷酸盐(4g碘kg−-1)可引起大鼠明显的蛋白渗出、肺水肿和动脉血氧分压下降。预先注射甲磺酸加贝酯(10和50 mg kg−，注射前5min)或甲磺酸那法莫斯特(3和10 mg kg−1)可逆转上述反应，其中注射甲磺酸那法莫斯特(10 mg kg−1)后抑制作用完全消失。甲磺酸加贝酯和甲磺酸那法莫他酯均能抑制纯化的人肺类胰蛋白酶的活性，但后者的作用远强于前者。Ioxagate可增强大鼠腹膜肥大细胞悬液胞外液纳法莫斯特敏感的蛋白水解酶活性。类胰蛋白酶可提高培养的人肺动脉内皮细胞单层蛋白质的通透性。氧磷酸盐与大鼠腹膜肥大细胞联合应用时，也会产生内皮屏障功能障碍。甲磺酸那法莫司他可逆转类胰蛋白酶和硫氰酸酯的上述作用。与这些发现一致的是，免疫荧光形态分析显示，类胰蛋白酶或Ioxagate与肥大细胞结合可增加肌动蛋白应激纤维的形成，同时降低VE-钙粘附素的免疫反应性。甲磺酸那法莫他汀可逆转类胰蛋白酶和硫代马汀的上述作用。这些发现表明，肥大细胞释放的类胰蛋白酶在异沙格酸盐所致的肺功能障碍中起着关键作用。在这方面，甲磺酸那法莫斯特可能成为治疗或预防放射造影剂严重不良反应的有用药物。
Intravenous injection of ioxaglate (4 g iodine kg−1), an iodinated radiographic contrast medium, caused a marked protein extravasation, pulmonary oedema and a decrease in the arterial partial oxygen pressure in rats. All of these reactions to ioxaglate were reversed by the pretreatment with gabexate mesilate (10 and 50 mg kg−1, 5 min prior to injection) or nafamostat mesilate (3 and 10 mg kg−1), in which the inhibition was complete after injection of nafamostat mesilate (10 mg kg−1). Both gabexate mesilate and nafamostat mesilate inhibited the activity of purified human lung tryptase, although the latter compound was far more potent than the former. Ioxaglate enhanced the nafamostat‐sensitive protease activity in the extracellular fluid of rat peritoneal mast cell suspensions. Tryptase enhanced the permeability of protein through the monolayer of cultured human pulmonary arterial endothelial cells. Ioxaglate, when applied in combination with rat peritoneal mast cells, also produced the endothelial barrier dysfunction. These effects of tryptase and ioxaglate were reversed by nafamostat mesilate. Consistent with these findings, immunofluorescence morphological analysis revealed that tryptase or ioxaglate in combination with mast cells increased actin stress fibre formation while decreasing VE‐cadherin immunoreactivity. Both of these actions of tryptase and ioxaglate were reversed by nafamostat mesilate. These findings suggest that tryptase liberated from mast cells plays a crucial role in the ioxaglate‐induced pulmonary dysfunction. In this respect, nafamostat mesilate may become a useful agent for the cure or prevention of severe adverse reactions to radiographic contrast media.
影响因子：
15.9
作者：
Corvera, CU;Dery, O;Bunnett, NW
通讯作者：
Bunnett, NW