α-Tocopherol Attenuates the Severity of <i>Pseudomonas aeruginosa</i> –induced Pneumonia

Abstract

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