Plasminogen activator inhibitor type 1 is protective during severe Gram-negative pneumonia.
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| 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.
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| Authors | Rosemarijn Renckens, Joris J T H Roelofs, Peter I Bonta, Sandrine Florquin, Carlie J M de Vries, Marcel Levi, Peter Carmeliet, Cornelis van't Veer, Tom van der Poll |
| Journal | Blood (Blood) Vol. 109 Issue 4 Pg. 1593-601 (Feb 15 2007) ISSN: 0006-4971 [Print] United States |
| PMID | 17032919 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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