Am J Physiol Lung Cell Mol Physiol. 2012 Oct 12. [Epub ahead of print]
Novel aspects of urokinase function in the injured lung: role of α2-macroglobulin.
Komissarov AA, Stankowska D, Krupa A, Fudala R, Florova G, Florence J, Fol M, Allen TC, Idell S, Matthay MA, Kurdowska AK.
Source
1The Texas Lung Injury Institute of The University of Texas Health Science Center at Tyler.
Abstract
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 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 cell (BEAS-2B), activation of nuclear factor κB as well as production of interleukin-6 and -8 was substantially suppressed compared to 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.
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