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.

中文翻译：

---

炭疽芽孢杆菌水肿毒素通过水肿因子和 cAMP 介导的机制抑制离体灌注大鼠肺的缺氧性肺血管收缩


在我们之前的研究中，炭疽杆菌水肿毒素 (ET) 抑制致命毒素刺激的肺动脉压力 (Ppa) 并增加肺 cAMP 水平。因此，我们检查了 ET 是否抑制缺氧性肺血管收缩 (HPV)。对健康大鼠的离体灌注肺进行基线缺氧测量后，与稀释剂相比，ET 灌注在 120 分钟 6 分钟缺氧期间 (FiO ₂ =0%) 减少了最大 Ppa 增加 [基线缺氧时最大 Ppa 增加的平均值 (±sem) 百分比] （16±6% vs. 51±6%，p=0.004）和 180 分钟（11.4% vs. 55±6%，p=0.001）。保护性抗原单克隆抗体 (PA-mAb) 和阿德福韦分别抑制宿主细胞水肿因子的摄取和 cAMP 的产生。在基线测量后用 ET 灌注的肺部中，与安慰剂相比，PA-mAb 治疗在 120 分钟和 180 分钟缺氧期间增加了 Ppa（分别为 56±6% vs. 10±4% 和 72±12% vs. 12±3%，p ≤0.01），阿德福韦也是如此（分别为 84±10% vs 16.8% 和 123±21% vs 26±11%，p≤0.01）。与稀释液相比，肺灌注180分钟ET降低了Ppa与内皮素-1（ET-1）浓度增加之间关系的斜率（21.12±2.96 vs. 3.00±0.76×10 ⁸ cmH ₂ O/M，p< 0 id=37>7 cmH ₂ O/M，p=0.005）添加到灌注液中。在用稀释剂、单独的 ET 或 ET 与 PA-m​​Ab 体内输注 15 小时后从大鼠分离的肺中，与稀释剂相比，缺氧期间的最大 Ppa 以及 Ppa 和添加到 ET-1 浓度的变化之间的关系斜率单独接受 ET 攻击的动物肺部灌注液减少 (p≤0.004)，但同时接受 ET 和 PA-m​​Ab 处理的动物肺部灌注液则没有减少 (p≥0.73)。 ET抑制HPV可加剧炭疽肺部感染期间的缺氧。