title: Plasminogen activator inhibitor type 1 is protective during severe Gram-negative pneumonia.
abstract: Plasminogen activator inhibitor type-1 (PAI-1) levels are consistently elevated in patients with severe pneumonia and sepsis and highly predictive for an unfavorable outcome. In addition, pneumonia is associated with strongly elevated PAI-1 levels in the pulmonary compartment. However, whether PAI-1 causally affects antibacterial host defense in vivo remains unknown. We report here that pneumonia caused by the common respiratory pathogen Klebsiella pneumoniae is associated with local production of PAI-1 in the lungs of wild-type mice. PAI-1 deficiency impaired host defense as reflected by enhanced lethality and increased bacterial growth and dissemination in mice with a targeted deletion of the PAI-1 gene. Conversely, transgenic overexpression of PAI-1 in the lung using a replication-defective adenoviral vector markedly improved host defense against Klebsiella pneumonia and sepsis. PAI-1 deficiency reduced accumulation of neutrophils in the lungs during pneumonia, whereas PAI-1 overexpression in healthy lungs resulted in neutrophil influx, suggesting that PAI-1 protects the host against Klebsiella pneumonia by promoting neutrophil recruitment to the pulmonary compartment. These data demonstrate for the first time that PAI-1 is essential for host defense against severe Gram-negative pneumonia.
authors.affiliation: Center for Infection and Immunity Amsterdam, Department of Pathology, University of Amsterdam, The Netherlands. r.renckens@amc.uva.nl
authors.forename: Rosemarijn
authors.initials: R
authors.lastname: Renckens
authors.forename: Joris J T H
authors.initials: JJ
authors.lastname: Roelofs
authors.forename: Peter I
authors.initials: PI
authors.lastname: Bonta
authors.forename: Sandrine
authors.initials: S
authors.lastname: Florquin
authors.forename: Carlie J M
authors.initials: CJ
authors.lastname: de Vries
authors.forename: Marcel
authors.initials: M
authors.lastname: Levi
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Cornelis
authors.initials: C
authors.lastname: van't Veer
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D000818:Animals; D006090:Gram-Negative Bacteria; D007711:Klebsiella pneumoniae / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000172:deficiency / Q000276:immunology*; D011014:Pneumonia / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D011379:Prognosis; D011652:Pulmonary Circulation / Q000276:immunology; D018805:Sepsis
chemical_list: D017395:Plasminogen Activator Inhibitor 1