Skin Pathology Induced by Snake Venom Metalloproteinase: Acute Damage, Revascularization, and Re-epithelization in a Mouse Ear Model

Abstract

Viperid snakebite envenomation induces blistering and dermonecrosis. The pathological alterations induced by a snake venom metalloproteinase in the skin were investigated in a mouse ear model. Metalloproteinase BaP1, from Bothrops asper, induced rapid edema, hemorrhage, and blistering; the latter two effects were abrogated by preincubation with the metalloproteinase inhibitor batimastat. Neutrophils did not play a role in the pathology, as depletion of these cells resulted in a similar histological picture. Blisters are likely to result from the direct proteolytic activity of BaP1 of proteins at the dermal-epidermal junction, probably at the lamina lucida, as revealed by immunostaining for type IV collagen and laminin. Widespread apoptosis of keratinocytes was detected by the TUNEL assay, whereas no apoptosis of capillary endothelial cells was observed. BaP1 induced a drastic reduction in the microvessel density, revealed by immunostaining for the endothelial marker vascular endothelial growth factor receptor-2. This was followed by a rapid angiogenic response, leading to a partial revascularization. Skin damage was followed by inflammation and granulation tissue formation. Then, a successful re-epithelization process occurred, and the skin of the ear regained its normal structure by 2 weeks. Venom metalloproteinase-induced skin damage reproduces the pathological changes described in snakebitten patients.

Experimental Bothrops atrox envenomation: Efficacy of antivenom therapy and the combination of Bothrops antivenom with dexamethasone

“…The SVMPs also participate strongly in the dermonecrosis by acting directly on the components of the connective tissue [37]. The SVMPs induce their effects by generating cytokines, such as TNF-α, through the cleavage of pro-TNF-α [38,39].…”

Mechanisms of Vascular Damage by Hemorrhagic Snake Venom Metalloproteinases: Tissue Distribution and In Situ Hydrolysis

“…Hemorrhagic and non-hemorrhagic SVMPs induce comparable rates of apoptosis in endothelial cells in culture [23] and the onset of hemorrhage induced by SVMPs occurs much earlier than the induction of apoptosis of endothelial cells in vitro . In addition, no apoptosis of endothelial cells was observed in SVMP-induced hemorrhage in the dermis of mouse ear skin, in vivo [24].…”

Biochemical and biological characterization of a dermonecrotic metalloproteinase isolated from Cerastes cerastes snake venom

“…Eschars and blistering induced by the venom and CcD‐II result from the separation of the dermis and the epidermis that leads to the disruption and the loss of epidermis that was observed in many regions of the affected skin tissue. These features are probably induced by the direct degradation of type IV collagen and laminin compounds involved in dermal–epidermal junctions at the lamina lucida region . Such skin tissue necrotic lesions were also described after bothropic envenomation …”