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

炭疽杆菌（B.炭疽病）仍然是发达国家的健康威胁。致死毒素和水肿毒素（分别为LT和ET）均参与炭疽感染时器官损伤和致死的发病机制。了解毒素致病作用的机制对于改善这种致命感染的结果将是重要的。体外研究结果确实表明，每种毒素都能引起内皮损伤和血管完整性丧失以及通透性增加。虽然从未在肺中进行过试验，但毒素增加的内皮渗透性可能导致液体外渗、氧转移和肺顺应性降低以及肺血管阻力增加。为了研究这些可能性，本研究将采用离体灌流大鼠肺模型来检查LT或ET是否确实引起肺内皮损伤和肺血管通透性增加。该离体模型将允许直接测量随时间变化的肺重量，这是计算肺渗透系数所需的。确定毒素是否改变肺通透性将提高我们对炭疽相关肺损伤的发病机制和临床管理的理解。 现在已经完成了关于这个项目的研究，并表明LT而不是ET增加了肺的通透性。LT也增加肺血管压力，但毒素渗透性的影响是独立的这些压力的变化。LT的作用是剂量依赖性的，它们被PA定向的单克隆抗体抑制。ET，这表明全身血管舒张作用否定了LT在肺动脉压中的增加，但不是其渗透性作用。这项工作于2018年出版。另外的研究已经完成与灌注肺模型显示，ET抑制缺氧性肺血管收缩的保护作用，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.