Transgenic tissue-type plasminogen activator expression improves host defense during Klebsiella pneumonia.
BACKGROUND
Severe pneumonia is associated with a local inhibition of fibrinolysis in the lung as reflected by strongly reduced pulmonary plasminogen activator activity.


OBJECTIVE
To study the effect of elevation of local plasminogen activator activity during pneumonia caused by the common respiratory pathogen Klebsiella pneumoniae.


METHODS
Female C57Bl/6 mice were inoculated intranasally with a replication-defective adenoviral vector expressing human tissue-type plasminogen activator or a control vector 24 h 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.
Renckens
R
R
Center for Infection and Immunity Amsterdam (CINIMA), and Center for Experimental and Molecular Medicine, University of Amsterdam, Amsterdam, The Netherlands. r.renckens@amc.uva.nl
Roelofs
J J T H
JJ
Stegenga
M E
ME
Florquin
S
S
Levi
M
M
Carmeliet
P
P
Van't Veer
C
C
van der Poll
T
T
D000256:Adenoviridae / Q000235:genetics*; D000281:Administration, Intranasal; D000818:Animals; D005260:Female; D005337:Fibrin / Q000032:analysis; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D005342:Fibrinolysis; D005822:Genetic Vectors / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology; D007710:Klebsiella Infections / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology*; D007711:Klebsiella pneumoniae / Q000302:isolation & purification; D008168:Lung / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018410:Pneumonia, Bacterial / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D018805:Sepsis / Q000517:prevention & control; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000502:physiology*; D019076:Transgenes
D005338:Fibrin Fibrinogen Degradation Products; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C036309:fibrin fragment D; D005337:Fibrin; D010959:Tissue Plasminogen Activator