title: PAI-1 is an essential component of the pulmonary host response during Pseudomonas aeruginosa pneumonia in mice.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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 1×10(7) 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.
authors.affiliation: Department of Anesthesiology, Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, USA.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Goolaerts
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lafargue
authors.forename: Yuanlin
authors.initials: Y
authors.lastname: Song
authors.forename: Byron
authors.initials: B
authors.lastname: Miyazawa
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Arjomandi
authors.forename: Michel
authors.initials: M
authors.lastname: Carlès
authors.forename: Jérémie
authors.initials: J
authors.lastname: Roux
authors.forename: Marybeth
authors.initials: M
authors.lastname: Howard
authors.forename: Dale A
authors.initials: DA
authors.lastname: Parks
authors.forename: Karen E
authors.initials: KE
authors.lastname: Iles
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Pittet
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis / Q000235:genetics*; D018410:Pneumonia, Bacterial / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D011552:Pseudomonas Infections / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000302:isolation & purification*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015415:Biomarkers; D017395:Plasminogen Activator Inhibitor 1; D004247:DNA