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

炭疽杆菌(B.anthracis，或称炭疽杆菌)仍然威胁着发达国家的健康。致死性毒素和水肿性毒素(分别为LT和ET)都参与了炭疽感染时器官损伤和致死性的发病机制。了解毒素致病作用的机制对于改善这种致命感染的结局将是重要的。体外研究结果确实表明，每种毒素都会导致内皮损伤、血管完整性丧失和通透性增加。尽管从未在肺中进行过测试，但毒素增加的内皮通透性可能会导致液体外渗，氧转移和肺顺应性减少，并增加肺血管阻力。为了研究这些可能性，本研究将使用一种隔离的大鼠肺灌流模型来检查LT或ET是否确实导致肺内皮损伤和肺血管通透性增加。这种体外模型将允许直接测量肺重量随时间的变化，这是计算肺通透系数所必需的。确定其中一种毒素是否会改变肺通透性，将有助于我们在临床上更好地了解炭疽相关性肺损伤的发病机制和治疗方法。 关于这一项目的研究现已完成，研究表明LT但ET可增加肺通透性。它也增加了肺血管压力，但毒素通透性的影响不依赖于这些压力变化。其作用呈剂量依赖关系，并可被PA导向的单抗抑制。ET，表明全身血管扩张效应抵消了LTS对肺动脉压的增加，但不能抵消其通透性效应。这部作品于2018年出版。另一项研究已经在肺灌流模型中完成，显示ET抑制缺氧性肺血管收缩的保护作用，一篇手稿正在审查中。

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.