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PAI-1 is an essential component of the pulmonary host response during Pseudomonas aeruginosa pneumonia in mice
  1. Arnaud Goolaerts1,*,
  2. Mathieu Lafargue1,*,
  3. Yuanlin Song1,*,
  4. Byron Miyazawa1,
  5. Mehrdad Arjomandi1,
  6. Michel Carlès2,
  7. Jérémie Roux1,
  8. Marybeth Howard1,
  9. Dale A Parks3,
  10. Karen E Iles3,
  11. Jean-François Pittet3
  1. 1Laboratory of Surgical Research, Departments of Anesthesia, Surgery & Medicine, Cardiovascular Research Institute & Institute of Molecular Medicine, University of California San Francisco, San Francisco, California, USA
  2. 2Department of Anesthesia and Critical Care, Nice University Hospital, University of Nice Sophia-Antipolis, France
  3. 3Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, Alabama, USA
  1. Correspondence to Dr Jean-Francois Pittet, Department of Anesthesiology, University of Alabama at Birmingham, 619 South 19th Street, JT926, Birmingham, AL 35249, USA; pittetj{at}


Rationale Elevated plasma and bronchoalveolar lavage fluid plasminogen activator inhibitor 1 (PAI-1) levels are associated with adverse clinical outcome in patients with pneumonia caused by Pseudomonas aeruginosa. However, whether PAI-1 plays a pathogenic role in the breakdown of the alveolar–capillary barrier caused by P aeruginosa is unknown.

Objectives The role of PAI-1 in pulmonary host defence and survival during P aeruginosa pneumonia in mice was tested. The in vitro mechanisms by which P aeruginosa causes PAI-1 gene and protein expression in lung endothelial and epithelial cells were also examined.

Methods and results PAI-1 null and wild-type mice that were pretreated with the PAI-1 inhibitor Tiplaxtinin had a significantly lower increase in lung vascular permeability than wild-type littermates after the airspace instillation of 1×107 colony-forming units (CFU) of P aeruginosa bacteria. Furthermore, P aeruginosa in vitro induced the expression of the PAI-1 gene and protein in a TLR4/p38/RhoA/NF-κB (Toll-like receptor 4/p38/RhoA/nuclear factor-κB) manner in lung endothelial and alveolar epithelial cells. However, in vivo disruption of PAI-1 signalling was associated with higher mortality at 24 h (p<0.03) and higher bacterial burden in the lungs secondary to decreased neutrophil migration into the distal airspace in response to P aeruginosa.

Conclusions The results indicate that PAI-1 is a critical mediator that controls the development of the early lung inflammation that is required for the activation of the later innate immune response necessary for the eradication of P aeruginosa from the distal airspaces of the lung.

  • PAI-1
  • P aeruginosa
  • pneumonia
  • RhoA
  • acute lung injury
  • airway epithelium
  • bacterial infection

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  • * AG, ML, and YS contributed equally to the manuscript.

  • Funding NIH grant GM086416 (to JFP), Belgian American Educational Foundation postdoctoral fellowship (to AG), Academic Senate Individual Investigator Grant, UCSF (to YS).

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.