Pseudomonas aeruginosa is a lethal pathogen that causes high mortality and morbidity in immunocompromised and critically ill patients. The type III secretion system (T3SS) of P. aeruginosa 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, P. aeruginosa T3SS exoenzyme (ExoY) intoxication into host cells, and survival in a murine model of pneumonia in the presence of P. aeruginosa and pretreatment with α-tocopherol. We found that α-tocopherol alleviated P. aeruginosa–mediated alveolar endothelial and epithelial paracellular permeability by inhibiting RhoA, in part, via PAI-1 activation, and increased survival in a mouse model of P. aeruginosa 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. P. aeruginosa 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 P. aeruginosa, such as those who are immunocompromised or critically ill.

铜绿假单胞菌是一种致死病原体，可导致免疫功能低下和危重患者的高死亡率和发病率。铜绿假单胞菌的III 型分泌系统 (T3SS)介导了该病原体感染的许多不利影响，包括 Toll 样受体 4/RhoA/PAI-1（纤溶酶原激活剂抑制剂-1）依赖性肺通透性增加方式。α-生育酚具有抗炎特性，可能使其成为治疗这种垂死感染的有用辅助剂。我们测量了跨内皮和跨上皮抵抗、RhoA 和 PAI-1 激活、应力纤维形成、铜绿假单胞菌T3SS 外酶 (ExoY) 中毒进入宿主细胞，以及在铜绿假单胞菌存在下肺炎鼠模型中的存活率并用α-生育酚预处理。我们发现，α-生育酚通过抑制 RhoA（部分通过 PAI-1 激活）来减轻铜绿假单胞菌介导的肺泡内皮和上皮细胞旁通透性，并增加铜绿假单胞菌肺炎小鼠模型的存活率。此外，我们发现 α-生育酚通过阻止 T3SS 外酶注入肺泡上皮细胞来降低 RhoA 和 PAI-1 的活化。铜绿假单胞菌对抗生素的抗药性越来越强。我们提供的证据表明，对于易感染铜绿假单胞菌的个体，例如免疫功能低下或危重患者，α-生育酚可能是一种有用的治疗剂。