Abstract
BackgroundEnvenomations by the snake Bothrops asper represent a serious medical problem in Central America and parts of South America. These envenomations concur with drastic local tissue pathology, including a prominent edema. Since lymph flow plays a role in the maintenance of tissue fluid balance, the effect of B. asper venom on collecting lymphatic vessels was studied.Methodology/Principal Findings B. asper venom was applied to mouse mesentery, and the effects were studied using an intravital microscopy methodology coupled with an image analysis program. B. asper venom induced a dose-dependent contraction of collecting lymphatic vessels, resulting in a reduction of their lumen and in a halting of lymph flow. The effect was reproduced by a myotoxic phospholipase A2 (PLA2) homologue isolated from this venom, but not by a hemorrhagic metalloproteinase or a coagulant thrombin-like serine proteinase. In agreement with this, treatment of the venom with fucoidan, a myotoxin inhibitor, abrogated the effect, whereas no inhibition was observed after incubation with the peptidomimetic metalloproteinase inhibitor Batimastat. Moreover, fucoidan significantly reduced venom-induced footpad edema. The myotoxic PLA2 homologue, known to induce skeletal muscle necrosis, was able to induce cytotoxicity in smooth muscle cells in culture and to promote an increment in the permeability to propidium iodide in these cells.Conclusions/SignificanceOur observations indicate that B. asper venom affects collecting lymphatic vessels through the action of myotoxic PLA2s on the smooth muscle of these vessels, inducing cell contraction and irreversible cell damage. This activity may play an important role in the pathogenesis of the pronounced local edema characteristic of viperid snakebite envenomation, as well as in the systemic biodistribution of the venom, thus representing a potential therapeutical target in these envenomations.
Highlights
Envenomations due to snakebites constitute a relevant, albeit neglected, health problem in many regions of the world, especially in rural areas of Africa, Asia, Latin America and Papua-New Guinea, where they have a high toll in terms of mortality and morbidity [1,2,3,4]
This study analyzed the effect of the venom of Bothrops asper, the most important venomous snake in Central America, on the collecting lymphatic vessels of the mouse mesentery
These effects were reproduced by a myotoxic phospholipase A2 homologue isolated from this venom, but not by a hemorrhagic metalloproteinase nor by a coagulant serine proteinase
Summary
Envenomations due to snakebites constitute a relevant, albeit neglected, health problem in many regions of the world, especially in rural areas of Africa, Asia, Latin America and Papua-New Guinea, where they have a high toll in terms of mortality and morbidity [1,2,3,4]. Owing to the size of this species, and to the large volume of venom that it delivers, these envenomations involve a prominent local pathology which includes edema, hemorrhage, blistering, dermonecrosis and myonecrosis [6,7,9]. The pathogenesis of these pathological alterations has been investigated in experimental models. These envenomations concur with drastic local tissue pathology, including a prominent edema. Since lymph flow plays a role in the maintenance of tissue fluid balance, the effect of B. asper venom on collecting lymphatic vessels was studied
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