Abstract
The historical development of discoveries and conceptual frames for understanding the hemorrhagic activity induced by viperid snake venoms and by hemorrhagic metalloproteinases (SVMPs) present in these venoms is reviewed. Histological and ultrastructural tools allowed the identification of the capillary network as the main site of action of SVMPs. After years of debate, biochemical developments demonstrated that all hemorrhagic toxins in viperid venoms are zinc-dependent metalloproteinases. Hemorrhagic SVMPs act by initially hydrolyzing key substrates at the basement membrane (BM) of capillaries. This degradation results in the weakening of the mechanical stability of the capillary wall, which becomes distended owing of the action of the hemodynamic biophysical forces operating in the circulation. As a consequence, the capillary wall is disrupted and extravasation occurs. SVMPs do not induce rapid toxicity to endothelial cells, and the pathological effects described in these cells in vivo result from the mechanical action of these hemodynamic forces. Experimental evidence suggests that degradation of type IV collagen, and perhaps also perlecan, is the key event in the onset of microvessel damage. It is necessary to study this phenomenon from a holistic, systemic perspective in which the action of other venom components is also taken into consideration.
Highlights
Snakebite envenoming constitutes a highly relevant, albeit largely neglected, public health problem on a global basis, affecting primarily impoverished populations in the rural settings of Africa, Asia, Latin America and parts of Oceania [1,2,3]
By observing the mesentery of rats using cinematographic techniques at the microscope, Ohsaka et al [40] described an initial vasoconstriction of arterioles, followed by vasodilation and by the extravasation of erythrocytes one by one through holes formed in the capillaries, but without an overt rupture of the endothelium. These findings suggested that hemorrhage occurs by extravasation of erythrocytes through openings in the intercellular endothelial cell junctions
It is clear that hemorrhage occurs mostly through the SVMP-induced degradation of key structural proteins at the basement membrane (BM) and its surroundings
Summary
Snakebite envenoming constitutes a highly relevant, albeit largely neglected, public health problem on a global basis, affecting primarily impoverished populations in the rural settings of Africa, Asia, Latin America and parts of Oceania [1,2,3]. The clinical manifestations of envenomings vary depending on the species of snake causing the bite, and there is a large spectrum of pathophysiological effects induced by snake venoms, owing to the diverse arsenal described in their composition [6]. Envenomings by snakes of the family Viperidae, and by some species of the family “Colubridae” (sensu lato), are characterized by prominent local and systemic hemorrhage. The study of the mechanism by which snake venoms induce hemorrhage and the characterization of hemorrhagic toxins and their mechanism of action has been a fascinating area of research within the field of Toxinology. The present contribution summarizes the journey of discovery and understanding that has led to our current view of snake venom-induced hemorrhage, and highlights some of the seminal discoveries and hypotheses generated during more than a century of scientific efforts
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