Novel aspects of urokinase function in the injured lung: role of α2-macroglobulin.
The level of active urokinase (uPA) is decreased in lung fluids of patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) whereas α(2)-macroglobulin (α(2)-M), a plasma proteinase inhibitor, is a major component of these fluids. Since there have been reports describing the ability of α(2)-M to form complexes with uPA in vitro, we hypothesized that α(2)-M may interact with uPA in the lung to modulate its biological activity. Pulmonary edema fluids and lung tissues from patients with ALI/ARDS were evaluated for the presence of uPA associated with α(2)-M. Complexes between α(2)-M and uPA were detected in alveolar edema fluids as well as in lungs of patients with ALI/ARDS where they were located mainly in close proximity to epithelial cells. While uPA bound to α(2)-M retains its amidolytic activity towards low-molecular-weight substrates, it is not inhibited by its main physiological inhibitor, plasminogen activator inhibitor 1. We also investigated the functional consequences of formation of complexes between uPA and α(2)-M in vitro. We found that when α(2)-M:uPA complexes were added to cultures of human bronchial epithelial cells (BEAS-2B), activation of nuclear factor-κB as well as production of interleukin-6 and -8 was substantially suppressed compared with the addition of uPA alone. Our findings indicate for the first time that the function of uPA in patients with ALI/ARDS may be modulated by α(2)-M and that the effects may include the regulation of the fibrinolytic and signaling activities of uPA.
Texas Lung Injury Institute, University of Texas Health Science Center, Tyler, Texas, USA.
Andrey A
AA
Komissarov
Dorota
D
Stankowska
Agnieszka
A
Krupa
Rafal
R
Fudala
Galina
G
Florova
Jon
J
Florence
Marek
M
Fol
Timothy C
TC
Allen
Steven
S
Idell
Michael A
MA
Matthay
Anna K
AK
Kurdowska
D055371:Acute Lung Injury / Q000378:metabolism*; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D016328:NF-kappa B / Q000378:metabolism; D011654:Pulmonary Edema / Q000378:metabolism*; D012128:Respiratory Distress Syndrome / Q000378:metabolism*; D015398:Signal Transduction; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis / Q000378:metabolism*; D000511:alpha-Macroglobulins / Q000378:metabolism*
C508606:CXCL8 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D000511:alpha-Macroglobulins; D014568:Urokinase-Type Plasminogen Activator