Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland.
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.
Am J Physiol Heart Circ Physiol. 2021 Jan 1;320(1):H36-H51. doi: 10.1152/ajpheart.00362.2020. Epub 2020 Oct 16.
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 with diluent, ET perfusion reduced maximal Ppa increases (mean ± SE percentage of maximal Ppa increase with baseline hypoxia) during 6-min hypoxic periods (FIO = 0%) at 120 min (16 ± 6% vs. 51 ± 6%, = 0.004) and 180 min (11.4% vs. 55 ± 6%, = 0.01). 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 with placebo, PA-mAb treatment increased Ppa during hypoxia at 120 and 180 min (56 ± 6% vs. 10 ± 4% and 72 ± 12% vs. 12 ± 3%, respectively, ≤ 0.01) as did adefovir (84 ± 10% vs. 16.8% and 123 ± 21% vs. 26 ± 11%, respectively, ≤ 0.01). Compared with diluent, lung perfusion with ET for 180 min 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 × 10 cmHO/M, < 0.0001) and U46619, a thromboxane A2 analogue (7.15 ± 1.01 vs. 3.74 ± 0.31 × 10 cmHO/M, = 0.05) added to perfusate. In lungs isolated from rats after 15 h of in vivo infusions with either diluent, ET alone, or ET with PA-mAb, compared with 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 ( ≤ 0.004) but not with ET and PA-mAb together ( ≥ 0.73). Inhibition of HPV by ET could aggravate hypoxia during anthrax pulmonary infection. The most important findings here are edema toxin's potent adenyl cyclase activity can interfere with hypoxic pulmonary vasoconstriction, an action that could worsen hypoxemia during invasive anthrax infection with lung involvement. These findings, coupled with other studies showing that lethal toxin can disrupt pulmonary vascular integrity, indicate that both toxins can contribute to pulmonary pathophysiology during infection. In combination, these investigations provide a further basis for the use of antitoxin therapies in patients with worsening invasive anthrax disease.
水肿毒素 (ET) 在我们之前的研究中抑制了致死毒素刺激的肺动脉压 (Ppa) 并增加了肺中的 cAMP 水平。因此，我们研究了 ET 是否抑制低氧性肺血管收缩 (HPV)。在来自健康大鼠的分离灌注肺的基础缺氧测量后，与稀释剂相比，ET 灌注在 120 分钟 (16 ± 6% 与 51 ± 6%， = 0.004) 和 180 分钟 (11.4% 与 55 ± 6%， = 0.01) 的 6 分钟缺氧期内降低了最大 Ppa 增加。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摄取和 cAMP 产生。在基线测量后用 ET 灌注的肺中，与安慰剂相比，PA-mAb 治疗在 120 和 180 分钟的缺氧期间增加了 Ppa (56 ± 6% 与 10 ± 4% 和 72 ± 12% 与 12 ± 3%，分别为 ≤ 0.01)，阿德福韦也是如此 (84 ± 10% 与 16.8% 和 123 ± 21% 与 26 ± 11%，分别为 ≤ 0.01)。与稀释剂相比，用 ET 灌注 180 分钟降低了 Ppa 与增加的内皮素-1 (ET-1) 浓度之间的关系斜率 (21.12 ± 2.96 与 3.00 ± 0.76 × 10 cmHO/M， < 0.0001) 和 U46619(血栓烷 A2 类似物)，加入灌流液 (7.15 ± 1.01 与 3.74 ± 0.31 × 10 cmHO/M， = 0.05)。在体内输注稀释剂、ET 单独或 ET 与 PA-mAb 15 小时后分离的大鼠肺中，与稀释剂相比，缺氧时的最大 Ppa 和添加到灌流液中的 ET-1 浓度变化与 Ppa 之间的关系斜率在仅接受 ET 挑战的动物的肺中降低 ( ≤ 0.004)，但在接受 ET 和 PA-mAb 一起接受挑战的动物的肺中没有降低 ( ≥ 0.73)。ET 对 HPV 的抑制作用可能会加重炭疽肺感染期间的缺氧。这里最重要的发现是水肿毒素的强大的腺苷酸环化酶活性可以干扰低氧性肺血管收缩，这一作用可能会在涉及肺的侵袭性炭疽感染期间导致低氧血症恶化。这些发现，加上其他研究表明致死毒素可以破坏肺血管完整性，表明两种毒素都可以导致感染期间的肺病理生理学变化。综合来看，这些研究为在病情恶化的侵袭性炭疽病患者中使用抗毒素疗法提供了进一步的依据。
