Crotoxin-Induced Mice Lung Impairment: Role of Nicotinic Acetylcholine Receptors and COX-Derived Prostanoids

Abstract

Respiratory compromise in Crotalus durissus terrificus (C.d.t.) snakebite is an important pathological condition. Considering that crotoxin (CTX), a phospholipase A2 from C.d.t. venom, is the main component of the venom, the present work investigated the toxin effects on respiratory failure. Lung mechanics, morphology and soluble markers were evaluated from Swiss male mice, and mechanism determined using drugs/inhibitors of eicosanoids biosynthesis pathway and autonomic nervous system. Acute respiratory failure was observed, with an early phase (within 2 h) characterized by enhanced presence of eicosanoids, including prostaglandin E2, that accounted for the increased vascular permeability in the lung. The alterations of early phase were inhibited by indomethacin. The late phase (peaked 12 h) was marked by neutrophil infiltration, presence of pro-inflammatory cytokines/chemokines, and morphological alterations characterized by alveolar septal thickening and bronchoconstriction. In addition, lung mechanical function was impaired, with decreased lung compliance and inspiratory capacity. Hexamethonium, a nicotinic acetylcholine receptor antagonist, hampered late phase damages indicating that CTX-induced lung impairment could be associated with cholinergic transmission. The findings reported herein highlight the impact of CTX on respiratory compromise, and introduce the use of nicotinic blockers and prostanoids biosynthesis inhibitors as possible symptomatic therapy to Crotalus durissus terrificus snakebite.

A Clot Twist: Extreme Variation in Coagulotoxicity Mechanisms in Mexican Neotropical Rattlesnake Venoms

“…The widespread presence of the neurotoxic phospholipase A 2 crotoxin in several species ( 33 – 37 ) places most Neotropical rattlesnakes (at least in early life stages) in the Type II venom category described by Mackessy ( 38 ). This class includes species possessing highly toxic venoms characterized by systemic neurotoxicity inducing rapid paralysis due to respiratory failure, rather than hemorrhagic symptoms ( 39 – 42 ). Conversely, phenotypes that are dominated by hemorrhagic and tissue-destroying snake venom metalloproteases (SVMPs) and generally devoid of neurotoxins are classified into the Type I category ( 38 ), which encompasses low-toxicity venoms inducing mostly cytotoxic and/or hemotoxic symptoms.…”

Crotalus Durissus Ruruima: Current Knowledge on Natural History, Medical Importance, and Clinical Toxinology

“…Local manifestations are commonly associated with the inflammatory properties that venom can trigger once inoculated. Although toxins from C. durissus subspecies are known to present low immunogenicity, studies have shown the capacity of venoms and toxins to promote local and systemic inflammatory responses in animal models ( 78 , 121 , 122 ). As previously described, C.d.…”

“…ruruima “yellow” and “white” venom variations are responsible for inducing mouse paw edema ( 112 ). Considering that the venom components crotoxin and serine proteases are found to trigger an inflammatory response ( 78 , 122 ), the higher frequency in local manifestations, such as edema, found in Roraima state could be associated with C. d. ruruima venom composition, in which the two toxins classes comprise over 90%. Moreover, although the low abundance of SVMP found in C. d. ruruima venom can be associated with rare cases of local sequelae, this group of toxins could be an additional factor for local injury as observed for North American Crotalus spp.…”

Crotalus Durissus Ruruima: Current Knowledge on Natural History, Medical Importance, and Clinical Toxinology

“…ruruima -yellow‖ and -white‖ venom variations are responsible for inducing mouse paw edema [112]. Considering that the venom components crotoxin and serine proteases are found to trigger an inflammatory response [78,122], the higher frequency in local manifestations, such as edema, found in Roraima state could be associated with C. d. ruruima venom composition, in which the two toxins classes comprise over 90%. Moreover, although the low abundance of SVMP found in C. d. ruruima venom can be associated with rare cases of local sequelae, this group of toxins could be an additional factor for local injury as observed for North American Crotalus spp.…”