Transgenic tissue-type plasminogen activator expression improves host defense during Klebsiella pneumonia

Abstract

Background: Severe pneumonia is associated with a local inhibition of fibrinolysis in the lung as reflected by strongly reduced pulmonary plasminogen activator activity. Objectives: To study the effect of elevation of local plasminogen activator activity during pneumonia caused by the common respiratory pathogen Klebsiella pneumoniae. Methods: Female C56Bl/6 mice were inoculated intranasally with a replication-defective adenoviral vector expressing human tissue-type plasminogen activator or a control vector 24h before intranasal infection with K. pneumoniae. Results: Mice infected with Klebsiella via the airways developed overt pneumonia, which was accompanied by a downregulation of pulmonary tissue-type plasminogen activator levels at protein and mRNA levels. Pulmonary overexpression of human tissue-type plasminogen activator resulted in increased fibrinolytic activity in the lungs during pneumonia, as indicated by higher D-dimer levels and reduced fibrin deposition. Interestingly, overexpression of tissue-type plasminogen activator markedly improved host defense against pneumonia: mice treated with the tissue-type plasminogen activator vector displayed less bacterial growth and dissemination, attenuated distant organ injury and a reduced mortality. Conclusions: These data demonstrate that local elevation of plasminogen activator activity in the lungs improves host defense against severe gram-negative pneumonia and sepsis. © 2008 International Society on Thrombosis and Haemostasis.