α-Tocopherol Attenuates the Severity of Pseudomonas aeruginosa-induced Pneumonia.

Abstract

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.

• Authors: Brant M Wagener, Naseem Anjum, Cilina Evans, Angela Brandon, Jaideep Honavar, Judy Creighton, Maret G Traber, Robert L Stuart, Troy Stevens, Jean-Francois Pittet
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 63 Issue 2 Pg. 234-243 (08 2020) ISSN: 1535-4989 [Electronic] United States
• PMID: 32243761 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Bacterial Proteins
• Plasminogen Activator Inhibitor 1
• Type III Secretion Systems
• rhoA GTP-Binding Protein
• alpha-Tocopherol

Topics

• Animals
• Bacterial Proteins (metabolism)
• Cells, Cultured
• Disease Models, Animal
• Endothelium (drug effects, metabolism)
• Humans
• Lung
• Mice
• Mice, Inbred C57BL
• Plasminogen Activator Inhibitor 1 (metabolism)
• Pneumonia (drug therapy)
• Pseudomonas Infections (drug therapy)
• Pseudomonas aeruginosa (drug effects, metabolism)
• Rats
• Type III Secretion Systems (drug effects)
• alpha-Tocopherol (pharmacology)
• rhoA GTP-Binding Protein (metabolism)