Pulmonary hemorrhage induced by jararhagin, a metalloproteinase from Bothrops jararaca snake venom
Pulmonary hemorrhage induced by jararhagin, a metalloproteinase from Bothrops jararaca snake venom
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DOI：
10.1016/s0041-008x(03)00337-5
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发表时间：
2003-11-15
影响因子：
3.8
通讯作者：
Gutiérrez, JM
中科院分区：
文献类型：
--
作者：
Escalante, T;Núñez, J;Gutiérrez, JM
Jararhagin是Bothrops jararaca毒液中最重要的出血成分，Bothrops jararaca是南美洲的一种重要的医学物种。它是一种P-III锌依赖性金属蛋白酶，包含催化、去整合素样和富含半胱氨酸的结构域。将Jararhagin静脉注射到小鼠中引起肺部快速和显著出血，而其他器官没有明显的出血表现。这种作用依赖于jararhagin的蛋白水解活性，因为它被合成抑制剂巴马司他消除。肺泡-毛细血管单位的细胞有明显的超微结构改变，即，毛细血管内皮细胞和I型肺细胞，具有与外渗相关的“局部肺泡损伤”的特征性模式。在全血凝固时间、出血时间和纤维蛋白原水平不受影响的条件下观察到这些病理学效应。静脉注射后，I-125标记的贾拉金主要集中在肝脏和肾脏中，在肺部观察到的放射性很小，从而表明肺微血管损伤的主导作用并不是由于该酶在肺部的优先浓度。尽管jararhagin在静脉注射后与血浆蛋白复合，但其出血活性不受血浆蛋白酶抑制剂α（2）-巨球蛋白的抑制，并且仅被正常小鼠血清部分降低，这表明对抑制的抵抗可能有助于其引起肺出血的能力。(C)2003年爱思唯尔公司All rights reserved.
Jararhagin is the most important hemorrhagic component in the venom of the snake Bothrops jararaca, a species of medical importance in South America. It is a P-III zinc-dependent metalloproteinase comprising catalytic, disintegrin-like, and cysteine-rich domains. Jararhagin injected intravenously into mice induced rapid and prominent bleeding in the lungs, whereas other organs were devoid of overt hemorrhagic manifestations. This action depends on the proteolytic activity of jararhagin, since it was abrogated by the synthetic inhibitor batimastat. There were conspicuous ultrastructural alterations in cells at the alveolo-capillary unit, i.e., capillary endothelial cells and type I pneumocytes, with a characteristic pattern of "regional alveolar damage" associated with extravasation. These pathological effects were observed under conditions in which the whole blood clotting time, bleeding time, and fibrinogen levels were not affected. I-125-labeled jararhagin is concentrated mainly in liver and kidneys after iv injection, with little radioactivity observed in the lungs, thereby indicating that the predominance of pulmonary microvascular damage is not due to a preferential concentration of this enzyme in the lungs. Despite the fact that jararhagin is complexed by plasma proteins after iv injection, its hemorrhagic activity was not inhibited by the plasma proteinase inhibitor alpha(2)-macroglobulin, and was only partially reduced by normal mouse serum, suggesting that resistance to inhibition may contribute to its ability to cause pulmonary hemorrhage. (C) 2003 Elsevier Inc. All rights reserved.