Abstract
The time-course of the pathological effects induced by the venom of the snake Bothrops asper in muscle tissue was investigated by a combination of histology, proteomic analysis of exudates collected in the vicinity of damaged muscle, and immunodetection of extracellular matrix proteins in exudates. Proteomic assay of exudates has become an excellent new methodological tool to detect key biomarkers of tissue alterations for a more integrative perspective of snake venom-induced pathology. The time-course analysis of the intracellular proteins showed an early presence of cytosolic and mitochondrial proteins in exudates, while cytoskeletal proteins increased later on. This underscores the rapid cytotoxic effect of venom, especially in muscle fibers, due to the action of myotoxic phospholipases A2, followed by the action of proteinases in the cytoskeleton of damaged muscle fibers. Similarly, the early presence of basement membrane (BM) and other extracellular matrix (ECM) proteins in exudates reflects the rapid microvascular damage and hemorrhage induced by snake venom metalloproteinases. The presence of fragments of type IV collagen and perlecan one hour after envenoming suggests that hydrolysis of these mechanically/structurally-relevant BM components plays a key role in the genesis of hemorrhage. On the other hand, the increment of some ECM proteins in the exudate at later time intervals is likely a consequence of the action of endogenous matrix metalloproteinases (MMPs) or of de novo synthesis of ECM proteins during tissue remodeling as part of the inflammatory reaction. Our results offer relevant insights for a more integrative and systematic understanding of the time-course dynamics of muscle tissue damage induced by B. asper venom and possibly other viperid venoms.
Highlights
The viperid snake Bothrops asper is responsible for most snakebite cases in Central America and some regions of Mexico and South America [1,2]
The local pathology induced by viperid snakes is characterized by a complex of alterations as consequence of direct and indirect effects of the toxins present in the venom, as well as the host response to tissue damage, and constitutes a dynamic process of degenerative and reparative events
The pathogenesis of local effects induced by Bothrops asper venom has been studied by traditional methodologies
Summary
The viperid snake Bothrops asper is responsible for most snakebite cases in Central America and some regions of Mexico and South America [1,2]. The local pathology induced by viperid snakes is characterized by edema, blistering, hemorrhage, lymphatic vessel damage, and necrosis of skin and muscle, some of which can be attributed to the degradation of extracellular matrix (ECM) [1,3]. Such alterations develop very rapidly after the bite, and in some cases can lead to permanent tissue damage, regardless of the application of antivenom treatment. The complexity of this pathology demands further analyses into hitherto unknown aspects of tissue damage and the complex interplay between degenerative and early reparative events. As envenoming is a dynamic event, it is critical to investigate the process over time, which is the main focus of this study
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