Plasminogen activator inhibitor type 1 is protective during severe Gram-negative pneumonia.
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.
Renckens
Rosemarijn
R
Center for Infection and Immunity Amsterdam, Department of Pathology, University of Amsterdam, The Netherlands. r.renckens@amc.uva.nl
Roelofs
Joris J T H
JJ
Bonta
Peter I
PI
Florquin
Sandrine
S
de Vries
Carlie J M
CJ
Levi
Marcel
M
Carmeliet
Peter
P
van't Veer
Cornelis
C
van der Poll
Tom
T
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
D017395:Plasminogen Activator Inhibitor 1