Investigation of anthrax lethal and edema toxins' pulmonary effects in an isolated perfused lung model

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Bacillus anthracis (B. anthracis or anthrax) remains a health threat for the developed world. Both lethal and edema toxin (LT and ET respectively) contribute to the pathogenesis of organ injury and lethality during anthrax infection. Understanding the mechanisms underlying the toxins pathogenic effects will be important for improving the outcome with this lethal infection. In vitro findings do suggest that each toxin can produce endothelial injury and loss of vascular integrity and increased permeability. Although never tested in the lung, increased endothelial permeability with the toxins could result in extravasation of fluid, reductions in oxygen transfer and lung compliance, and increased pulmonary vascular resistance. To investigate these possibilities, the present study will employ an isolated perfused rat lung model to examine whether LT or ET does cause pulmonary endothelial injury and increased pulmonary vascular permeability. This ex vivo model will allow a direct measure of changing lung weight over time, which is required to calculate a lung permeability coefficient. Determining whether either toxin alters lung permeability will improve our understanding of the pathogenesis and management of anthrax associated lung injury clinically. Studies have now been completed on this project and show that LT but ET increases lung permeability. LT also increased pulmonary vascular pressures but the toxins permeability effects were independent of these pressure changes. LTs effects were dose dependent and they were inhibited with a PA directed monoclonal antibody. ET, which have shown that systemic vasodilatory effects negated LTs increases in pulmonary artery pressures but not its permeability effects. This work was published in 2018. Additional study has been completed with the perfused lung model showing that ET inhibits the protective effects of hypoxic pulmonary vasoconstriction and a manuscript is under review.