Bbeta(15-42) protects against acid-induced acute lung injury and secondary pseudomonas pneumonia in vivo.
BACKGROUND
Acute lung injury (ALI) is a serious condition in critically ill patients that predisposes to secondary bacterial pneumonia. Vascular leak is a hallmark in the pathogenesis of ALI. The fibrin-derived peptide Bbeta(15-42) was shown to preserve endothelial barriers, thereby reducing vascular leak. The potential therapeutic role of Bbeta(15-42) in ALI has not been addressed so far.


OBJECTIVE
To investigate the therapeutic potential of Bbeta(15-42) in ALI and secondary pneumonia induced by Pseudomonas aeruginosa.


METHODS
The effect of the fibrin-derived peptide Bbeta(15-42) was studied in models of ALI, induced either by pulmonary administration of LPS or hydrochloric acid. Lung inflammation was analyzed by quantifying cell influx, cytokine levels, and oxidized lipids. Vascular leak was determined by Evans Blue extravasations and alveolar protein content. In subsequent two-hit studies, mice were infected with P. aeruginosa 24 hours after induction of aspiration pneumonitis and effects of Bbeta(15-42) on inflammation, bacterial clearance, and survival were evaluated.


RESULTS
After LPS or acid inhalation, proinflammatory cytokine levels, neutrophil influx, and vascular leak were found diminished in mice treated with Bbeta(15-42). Acid aspiration impaired macrophage functions and rendered mice more susceptible to subsequent P. aeruginosa infection, whereas mice that received Bbeta(15-42) during acid aspiration and were subsequently challenged with bacteria displayed reduced inflammation, enhanced bacterial clearance, and ultimately improved survival.


CONCLUSIONS
The fibrin-derived peptide Bbeta(15-42) exerted protective effects during ALI, resulting in diminished lung injury and preserved antibacterial properties of macrophages, which improved outcome during subsequent P. aeruginosa pneumonia.
Matt
Ulrich
U
Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), Vienna, Austria.
Warszawska
Joanna Maria
JM
Bauer
Michael
M
Dietl
Wolfgang
W
Mesteri
Ildiko
I
Doninger
Bianca
B
Haslinger
Isabella
I
Schabbauer
Gernot
G
Perkmann
Thomas
T
Binder
Christoph J
CJ
Reingruber
Sonja
S
Petzelbauer
Peter
P
Knapp
Sylvia
S
D055371:Acute Lung Injury / Q000139:chemically induced / Q000150:complications / Q000517:prevention & control*; D000818:Animals; D004195:Disease Models, Animal; D005338:Fibrin Fibrinogen Degradation Products / Q000627:therapeutic use*; D006851:Hydrochloric Acid; D007249:Inflammation / Q000517:prevention & control; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000627:therapeutic use*; D018410:Pneumonia, Bacterial / Q000150:complications / Q000382:microbiology / Q000517:prevention & control*; D011552:Pseudomonas Infections / Q000150:complications / Q000382:microbiology / Q000517:prevention & control*; D011550:Pseudomonas aeruginosa; D016019:Survival Analysis; D016896:Treatment Outcome
D005338:Fibrin Fibrinogen Degradation Products; D008070:Lipopolysaccharides; D010446:Peptide Fragments; C033786:fibrinogen Bbeta (15-42); D006851:Hydrochloric Acid