Role of inflammation in the pulmonary hemorrhage induced by a snake venom metalloproteinase

Abstract Snakebite envenoming (a neglected tropical disease that affects millions of people worldwide every year) is characterized by a complex pathophysiology. In cases of viperid envenomings, local and systemic hemorrhage is one of the major systemic effects that manifest in patients. This work focuses on studying pulmonary hemorrhage caused by a type P-III snake venom metalloproteinase (SVMP) extracted from Crotalus simus venom, and the extent to which inflammation affects the outcome of this hemorrhage. In order to determine the role of inflammation in pulmonary hemorrhage, we created a new automated image analysis methodology using the CellProfiler platform to quantitatively assess hemorrhage under different conditions, in conjunction with a statistical analysis program to process and analyze said image analysis results. With this toolset, we subsequently analyzed hemorrhage under the effects of treatment with three anti-inflammatory agents (a COX inhibitor, a TNF-ɑ inhibitor, and anti-neutrophil antibodies) in combination with the toxin on a murine model. Our findings conclude that inhibiting inflammation reduced lung hemorrhage significantly, which shows promise as a potential novel avenue for the treatment of snake envenomings. Moreover, we propose new hypotheses for how the toxin may enter lung capillaries and subsequently cause basement membrane damage which eventually leads to lung hemorrhage. This study was supported by Vicerrectori?a de Investigación, Universidad de Costa Rica (Project 741-B4-524), and by a fund for support of graduate studies of the Sistema de Estudios de Posgrado (Universidad de Costa Rica)