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. Novel aspects of urokinase function in the injured lung: role of alpha(2)-macroglobulin. Am J Physiol Lung Cell Mol Physiol 303: L1037-L1045, 2012. First published October 12, 2012; doi: 10.1152/ajplung.00117.2012.-The level of active urokinase (uPA) is decreased in lung fluids of patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) whereas alpha(2)-macroglobulin (alpha(2)-M), a plasma proteinase inhibitor, is a major component of these fluids. Since there have been reports describing the ability of alpha(2)-M to form complexes with uPA in vitro, we hypothesized that alpha(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 alpha(2)-M. Complexes between alpha(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 alpha(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 alpha(2)-M in vitro. We found that when alpha(2)-M: uPA complexes were added to cultures of human bronchial epithelial cells (BEAS-2B), activation of nuclear factor-kappa B 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 alpha(2)-M and that the effects may include the regulation of the fibrinolytic and signaling activities of uPA.