Abstract
Viperid snakebite envenomation is characterized by inflammatory events including increase in vascular permeability. A copious exudate is generated in tissue injected with venom, whose proteomics analysis has provided insights into the mechanisms of venom-induced tissue damage. Hereby it is reported that wound exudate itself has the ability to induce increase in vascular permeability in the skin of mice. Proteomics analysis of exudate revealed the presence of cytokines and chemokines, together with abundant damage associated molecular pattern molecules (DAMPs) resulting from both proteolysis of extracellular matrix and cellular lysis. Moreover, significant differences in the amounts of cytokines/chemokines and DAMPs were detected between exudates collected 1 h and 24 h after envenomation, thus highlighting a complex temporal dynamic in the composition of exudate. Pretreatment of mice with Eritoran, an antagonist of Toll-like receptor 4 (TLR4), significantly reduced the exudate-induced increase in vascular permeability, thus suggesting that DAMPs might be acting through this receptor. It is hypothesized that an “Envenomation-induced DAMPs cycle of tissue damage” may be operating in viperid snakebite envenomation through which venom-induced tissue damage generates a variety of DAMPs which may further expand tissue alterations.
Highlights
Envenomation by viperid snakes causes local and systemic pathological and pathophysiological manifestations [1,2]
Several years ago we described in animal models of envenomation that there is a copious volume of wound exudate at the site of tissue damage [5,8]
When exudates collected from animals treated with B. asper venom were injected intradermally in the skin of mice, they induced an increase in vascular permeability, as reflected by the extravasation of
Summary
Envenomation by viperid snakes causes local and systemic pathological and pathophysiological manifestations [1,2]. Markers for disease and various pathological conditions are often best observed in proximity to the site of tissue damage As such we utilized venom-induced wound exudate for proteomic exploration of the effects of whole venom and isolated toxins, as well as neutralization by antivenoms and toxin inhibitors, to gain insight into the biological mechanisms by which these agents in vivo give rise to the symptoms and pathologies observed during snakebite envenomation [15,16,17]. These studies, in addition to illuminating many aspects of toxin action, demonstrated that venom-induced wound exudate is a very rich reservoir of various inflammatory mediators and of damage-associated (or danger-associated) molecular pattern molecules (DAMPs). Some of the DAMPs are derived from the proteolysis of host proteins by the SVMPs and activated endogenous host proteinases and some the result of cell lysis and the escape of cellular proteins into the exudate due to cytotoxic phopholipases A2 present in the venom [15]
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