Department of Anesthesiology and Perioperative Medicine.
Center for Free Radical Biology, and.
Am J Respir Cell Mol Biol. 2020 Aug;63(2):234-243. doi: 10.1165/rcmb.2019-0185OC.
is a lethal pathogen that causes high mortality and morbidity in immunocompromised and critically ill patients. The type III secretion system (T3SS) of mediates many of the adverse effects of infection with this pathogen, including increased lung permeability in a Toll-like receptor 4/RhoA/PAI-1 (plasminogen activator inhibitor-1)-dependent manner. α-Tocopherol has antiinflammatory properties that may make it a useful adjunct in treatment of this moribund infection. We measured transendothelial and transepithelial resistance, RhoA and PAI-1 activation, stress fiber formation, T3SS exoenzyme (ExoY) intoxication into host cells, and survival in a murine model of pneumonia in the presence of and pretreatment with α-tocopherol. We found that α-tocopherol alleviated -mediated alveolar endothelial and epithelial paracellular permeability by inhibiting RhoA, in part, via PAI-1 activation, and increased survival in a mouse model of pneumonia. Furthermore, we found that α-tocopherol decreased the activation of RhoA and PAI-1 by blocking the injection of T3SS exoenzymes into alveolar epithelial cells. is becoming increasingly antibiotic resistant. We provide evidence that α-tocopherol could be a useful therapeutic agent for individuals who are susceptible to infection with , such as those who are immunocompromised or critically ill.
是一种致命病原体，可导致免疫功能低下和重症患者高死亡率和发病率。 mediates 感染这种病原体的许多不良影响，包括以 Toll 样受体 4/RhoA/PAI-1（纤溶酶原激活物抑制剂-1）依赖性方式增加肺通透性。 α-生育酚具有抗炎特性，使其成为治疗这种濒死感染的有用辅助手段。我们测量了跨内皮和跨上皮电阻、RhoA 和 PAI-1 激活、应激纤维形成、 T3SS 外分泌酶 (ExoY) 对宿主细胞的中毒以及在肺炎的小鼠模型中存在 和用 α-生育酚预处理后的存活率。我们发现 α-生育酚通过抑制 RhoA 缓解了介导的肺泡内皮和上皮细胞旁通透性，部分通过 PAI-1 激活，并且增加了肺炎的小鼠模型中的存活率。此外，我们发现 α-生育酚通过阻止 T3SS 外分泌酶注入肺泡上皮细胞来减少 RhoA 和 PAI-1 的激活。 对抗生素的耐药性越来越强。我们提供的证据表明，α-生育酚可能是对 感染易感的个体（如免疫功能低下或重症患者）的有用治疗剂。
