The biochemical characteristics of hemorrhagic
metalloproteinases isolated from
snake venoms are reviewed, together with their role in the pathogenesis of the local tissue damage characteristic of crotaline and viperine
snake envenomations.
Venom metalloproteinases differ in their domain structure. Some
enzymes comprise only the
metalloproteinase domain, others have
disintegrin-like and high
cysteine domains and others present, besides these domains, an additional
lectin-like subunit. All of them are
zinc-dependent
enzymes with highly similar
zinc binding environments. Some
metalloproteinases induce
hemorrhage by directly affecting mostly capillary blood vessels. It is suggested that hemorrhagic
enzymes cleave, in a highly selective fashion, key
peptide bonds of basement membrane components, thereby affecting the interaction between basement membrane and endothelial cells. As a consequence, these cells undergo a series of morphological and functional alterations in vivo, probably associated with biophysical hemodynamic factors such as tangential fluid shear stress. Eventually, gaps are formed in endothelial cells through which extravasation occurs. In addition to
hemorrhage,
venom metalloproteinases induce skeletal muscle damage, myonecrosis, which seems to be secondary to the
ischemia that ensues in muscle tissue as a consequence of
bleeding and reduced perfusion. Microvessel disruption by
metalloproteinases also impairs skeletal muscle regeneration, being therefore responsible of
fibrosis and permanent tissue loss after
snakebites. Moreover,
venom metalloproteinases participate in the degradation of extracellular matrix components and play a relevant role in the prominent local inflammatory response that characterizes
snakebite envenomations, since they induce
edema, activate endogenous
matrix metalloproteinases (
MMPs) and are capable of releasing
TNF-alpha from its membrane-bound precursor. Owing to their protagonic role in the pathogenesis of local tissue damage,
snake venom metalloproteinases constitute relevant targets for natural and synthetic inhibitors which may
complement antivenoms in the neutralization of these effects.