Mechanisms of Vascular Damage by Hemorrhagic Snake Venom Metalloproteinases: Tissue Distribution and In Situ Hydrolysis
Mechanisms of Vascular Damage by Hemorrhagic Snake Venom Metalloproteinases: Tissue Distribution and In Situ Hydrolysis
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DOI：
10.1371/journal.pntd.0000727
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发表时间：
2010-06-01
影响因子：
3.8
通讯作者：
Moura-da-Silva, Ana M.
中科院分区：
文献类型：
--
作者：
Baldo, Cristiani;Jamora, Colin;Moura-da-Silva, Ana M.
40.在巴西和其他发展中国家，毒蛇的毒化是一个重要的公共卫生问题。局部出血是这些事故的重要症状，并与蛇毒金属蛋白酶（SVMP）的作用有关。血管基底膜的降解被认为是毛细血管破裂的关键事件。然而，对细胞外基质蛋白具有相似催化活性的SVMP在其出血活性方面有所不同，这表明其他机制可能有助于SVMP在蛇咬伤区域的积累，从而导致毛细血管破裂。在这项工作中，我们比较了jararhagin诱导的细胞外基质蛋白的组织分布和降解（高出血性SVMP）和BnP 1（弱出血性SVMP）。Jararhagin诱导强烈出血伴随着下皮胶原纤维的水解和血管基底膜IV型胶原的显著降解。相反，BnP 1仅诱导轻度出血，不破坏胶原纤维或IV型胶原。注射Alexa 488标记的jararhagin显示毛细血管周围的荧光染色和与基底膜IV型胶原共定位。用jararhagin-C（jararhagin的去整合素样/富含半胱氨酸的结构域）检测到相同的分布模式。相反，BnP 1没有积累在tissues.Conclusions/Significance：这些结果显示出血毒素积累在基底膜的特定组织分布。这可能是通过与胶原蛋白结合而发生的，胶原蛋白在出血性病变部位急剧水解。血管附近的毒素积累解释了基底膜组分的催化增强，导致SVMP的强出血活性。这是一种新的机制，是出血性和非出血性SVMP之间差异的基础，提高了对蛇咬伤病理学的理解。
Background: Envenoming by viper snakes constitutes an important public health problem in Brazil and other developing countries. Local hemorrhage is an important symptom of these accidents and is correlated with the action of snake venom metalloproteinases (SVMPs). The degradation of vascular basement membrane has been proposed as a key event for the capillary vessel disruption. However, SVMPs that present similar catalytic activity towards extracellular matrix proteins differ in their hemorrhagic activity, suggesting that other mechanisms might be contributing to the accumulation of SVMPs at the snakebite area allowing capillary disruption.Methodology/Principal Findings: In this work, we compared the tissue distribution and degradation of extracellular matrix proteins induced by jararhagin (highly hemorrhagic SVMP) and BnP1 (weakly hemorrhagic SVMP) using the mouse skin as experimental model. Jararhagin induced strong hemorrhage accompanied by hydrolysis of collagen fibers in the hypodermis and a marked degradation of type IV collagen at the vascular basement membrane. In contrast, BnP1 induced only a mild hemorrhage and did not disrupt collagen fibers or type IV collagen. Injection of Alexa488-labeled jararhagin revealed fluorescent staining around capillary vessels and co-localization with basement membrane type IV collagen. The same distribution pattern was detected with jararhagin-C (disintegrin-like/cysteine-rich domains of jararhagin). In opposition, BnP1 did not accumulate in the tissues.Conclusions/Significance: These results show a particular tissue distribution of hemorrhagic toxins accumulating at the basement membrane. This probably occurs through binding to collagens, which are drastically hydrolyzed at the sites of hemorrhagic lesions. Toxin accumulation near blood vessels explains enhanced catalysis of basement membrane components, resulting in the strong hemorrhagic activity of SVMPs. This is a novel mechanism that underlies the difference between hemorrhagic and non-hemorrhagic SVMPs, improving the understanding of snakebite pathology.