Bacillus anthracis lethal toxin, but not edema toxin, increases pulmonary artery pressure and permeability in isolated perfused rat lungs

Although lethal toxin (LT) and edema toxin (ET) contribute to lethality during infection, whether they increase vascular permeability and the extravascular fluid accumulation characterizing this infection is unclear. We employed an isolated perfused Sprague-Dawley rat lung model to investigate LT and ET effects on pulmonary vascular permeability. Lungs ( ≥ 6 per experimental group) were isolated, ventilated, suspended from a force transducer, and perfused. Lung weight and pulmonary artery (P ) and left atrial pressures were measured over 4 h, after which pulmonary capillary filtration coefficients (Kf.c) and lung wet-to-dry weight ratios (W/D) were determined. When compared with controls, LT increased P over 4 h and Kf.c and W/D at 4 h ( < 0.0001). ET decreased P in a significant trend ( = 0.09) but did not significantly alter Kf.c or W/D ( ≥ 0.29). Edema toxin actually blocked LT increases in P but not LT increases in Kf.c and W/D. When P was maintained at control levels, LT still increased Kf.c and W/D ( ≤ 0.004). Increasing the dose of each toxin five times significantly increased and a toxin-directed monoclonal antibody decreased the effects of each toxin ( ≤ 0.05). Two rho-kinase inhibitors (GSK269962 and Y27632) decreased LT increases in P ( ≤ 0.02) but actually increased Kf.c and W/D in LT and control lungs ( ≤ 0.05). A vascular endothelial growth factor receptor inhibitor (ZM323881) had no significant effect ( ≥ 0.63) with LT. Thus, LT but not ET can increase pulmonary vascular permeability independent of increased P and could contribute to pulmonary fluid accumulation during anthrax infection. However, pulmonary vascular dilation with ET could disrupt protective hypoxic vasoconstriction. The most important findings from the present study are that lethal toxin increases pulmonary artery pressure and pulmonary permeability independently in the isolated rat lung, whereas edema toxin decreases the former and does not increase permeability. Each effect could be a basis for organ dysfunction in patients with this lethal infection. These findings further support the need for adjunctive therapies that limit the effects of both toxins during infection.