Basement membrane degradation and inflammation play a role in the pulmonary hemorrhage induced by a P-III snake venom metalloproteinase. (15th July 2021)

• Record Type: Journal Article
• Authors: Castro, Ana Cristina; Escalante, Teresa; Rucavado, Alexandra; Gutiérrez, José María
• Is Part Of: Toxicon. Volume 197(2021)
• Page Start: 12
• Page End: 23
• Publication Date: 2021-07-15
• Subjects: Snake venom metalloproteinases (SVMPs) -- Pulmonary hemorrhage -- Basement membrane degradation -- Lung inflammation -- Neutrophils -- Bronchoalveolar lavage fluid; Toxins -- Periodicals; Venom -- Periodicals; 615.9
• DOI: 10.1016/j.toxicon.2021.04.012
• Languages: English
• ISSNs: 0041-0101

Abstract

Abstract: Snakebite envenoming is a neglected tropical disease affecting millions of people every year, especially in vulnerable rural populations in the developing world. Viperid snakes cause envenomings characterized by a complex pathophysiology which includes local and systemic hemorrhage due to the action of snake venom metalloproteinases (SVMPs). The pathogenesis of SVMP-induced systemic hemorrhage has not been investigated in detail. This study explored the pulmonary hemorrhage induced in a murine model by a P-III SVMP from the venom of Crotalus simus . Histological analysis revealed extravasation in the lungs as early as 15 min after intravenous injection of the toxin, and hemorrhage increased at 360 min. Western blot analysis demonstrated the cleavage of basement membrane (BM) proteins in lung homogenates and in bronchoalveolar lavage fluid, implying an enzymatic disruption of this extracellular matrix structure at the capillary-alveolar barrier. Likewise, alveolar edema was observed, with an increment in protein concentration in the bronchoalveolar lavage fluid, and a neutrophil-rich inflammatory infiltrate was present in the parenchyma of the lungs as part of the inflammatory reaction. Pretreatment of mice with indomethacin, pentoxifylline and an anti-neutrophil antibody resulted in a significant decrease in pulmonary hemorrhage at 360 min. These findings suggest that this P-III SVMP induces acute lung injury through the direct action of this enzyme in the capillary-alveolar barrier integrity, as revealed by BM degradation, and as a consequence of the inflammatory reaction that develops in lung tissue. Our findings provide novel clues to understand the mechanism of action of hemorrhagic SVMPs in the lungs. Graphical abstract: Image 1 Highlights: A P-III hemorrhagic metalloproteinase from Crotalus simus venom induces hemorrhage of rapid onset in the lungs in mice. There is enzymatic degradation of pulmonary basement membrane components as soon as 15 min after toxin injection. An inflammatory reaction develops in the lungs as a consequence of the action of CsH1. The administration of indomethacin, pentoxifylline, and anti-neutrophil antibodies reduced the extent of hemorrhage. Hemorrhage results from a direct action of CsH1 in the pulmonary vasculature and from the effect of inflammation.