Bacillus anthracis edema toxin inhibits hypoxic pulmonary vasoconstriction via edema factor and cAMP-mediated mechanisms in isolated perfused rat lungs

Abstract

Bacillus anthracis edema toxin (ET) inhibited lethal toxin stimulated pulmonary artery pressure (Ppa) and increased lung cAMP levels in our previous study. We therefore examined whether ET inhibits hypoxic pulmonary vasoconstriction (HPV). Following baseline hypoxic measures in isolated perfused lungs from healthy rats, compared to diluent, ET perfusion reduced maximal Ppa increases [mean(±sem) percent of maximal Ppa increase with baseline hypoxia] during 6min hypoxic periods (FiO2=0%) at 120min (16±6% vs. 51±6%, p=0.004) and 180min (11.4% vs. 55±6%, p=0.001). Protective antigen-mAb (PA-mAb) and adefovir inhibit host cell edema factor uptake and cAMP production respectively. In lungs perfused with ET following baseline measures, compared to placebo, PA-mAb treatment increased Ppa during hypoxia at 120 and 180min (56±6% vs. 10±4% and 72±12% vs. 12±3% respectively, p≤0.01) as did adefovir (84±10% vs 16.8% and 123±21% vs. 26±11%, respectively, p≤0.01). Compared to diluent, lung perfusion with ET for 180min reduced the slope of the relationships between Ppa and increasing concentrations of endothelin-1 (ET-1)(21.12±2.96 vs. 3.00±0.76×108cmH2O/M, p<0.0001) and U46619, a thromboxane A2 analogue (7.15±1.01 vs. 3.74±0.31×107cmH2O/M, p=0.005) added to perfusate. In lungs isolated from rats after 15h of in vivo infusions with either diluent, ET alone or ET with PA-mAb, compared to diluent, the maximal Ppa during hypoxia and the slope of the relationship between change in Ppa and ET-1 concentration added to the perfusate were reduced in lungs from animals challenged with ET alone (p≤0.004) but not with ET and PA-mAb together (p≥0.73). Inhibition of HPV by ET could aggravate hypoxia during anthrax pulmonary infection.