Abstract
BackgroundViperid snakebite envenoming is characterized by prominent local tissue damage, including muscle necrosis. A frequent outcome of such local pathology is deficient skeletal muscle regeneration, which causes muscle dysfunction, muscle loss and fibrosis, thus provoking permanent sequelae that greatly affect the quality of life of patients. The causes of such poor regenerative outcome of skeletal muscle after viperid snakebites are not fully understood.Methodology/Principal FindingsA murine model of muscle necrosis and regeneration was adapted to study the effects of the venom and isolated toxins of Bothrops asper, the medically most important snake in Central America. Gastrocnemius muscle was injected with either B. asper venom, a myotoxic phospholipase A2 (Mtx), a hemorrhagic metalloproteinase (SVMP), or saline solution. At various time intervals, during one month, tissue samples were collected and analyzed by histology, and by immunocytochemical and immunohistochemical techniques aimed at detecting muscle fibers, collagen, endothelial cells, myoblasts, myotubes, macrophages, TUNEL-positive nuclei, and axons. A successful regenerative response was observed in muscle injected with Mtx, which induces myonecrosis but does not affect the microvasculature. In contrast, poor regeneration, with fibrosis and atrophic fibers, occurred when muscle was injected with venom or SVMP, both of which provoke necrosis, microvascular damage leading to hemorrhage, and poor axonal regeneration.Conclusions/SignificanceThe deficient skeletal muscle regeneration after injection of B. asper venom is likely to depend on the widespread damage to the microvasculature, which affects the removal of necrotic debris by phagocytes, and the provision of nutrients and oxygen required for regeneration. In addition, deficient axonal regeneration is likely to contribute to the poor regenerative outcome in this model.
Highlights
Snakebite envenomings constitute a highly relevant and neglected public health problem on a world wide basis, affecting the rural settings of Latin America, Africa and Asia [1,2,3]
In the case of muscle injected with venom or BaP1, hemorrhage was observed, whereas no hemorrhage was induced by myotoxic phospholipase A2 (Mtx)
Fibrosis was corroborated 7 days after injection, by staining with Sirius Red, in the endomysium and perimysium in muscle injected with venom or BaP1 (Fig 1), whereas the extent of collagen deposition was less evident in Mtx-injected muscle, being higher than in PBS-injected muscle
Summary
Snakebite envenomings constitute a highly relevant and neglected public health problem on a world wide basis, affecting the rural settings of Latin America, Africa and Asia [1,2,3]. In Latin America, the majority of snakebites are inflicted by species classified in the genus Bothrops [4,5] These envenomings are characterized by complex pathological and pathophysiological profiles that include prominent local tissue damage, i.e. necrosis, hemorrhage, blistering and edema, and systemic alterations, i.e. bleeding, coagulopathy, cardiovascular shock and renal failure [6,7,8,9,10]. Among these effects, local tissue damage leading to necrosis is relevant, since it is frequently followed by poor tissue regeneration, with the occurrence of permanent sequelae associated with tissue loss and dysfunction, and their consequent social and psychological implications [1,11,12]. The causes of such poor regenerative outcome of skeletal muscle after viperid snakebites are not fully understood
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