Submitted May 23, 2006
Accepted September 25, 2006
Plasminogen activator inhibitor type 1 is protective during severe Gram-negative pneumonia
Rosemarijn Renckens*, Joris J.T.H, Roelofs, Peter I. Bonta, Sandrine Florquin, Carlie J. M. de Vries, Marcel M. Levi, Peter Carmeliet, Cornelis van 't Veer, and Tom van der Poll
Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Netherlands
Academic Medical Center, University of Amsterdam, Netherlands
University of Leuven, Belgium
* Corresponding author; email: r.renckens{at}amc.uva.nl.
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.
