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 α₂macroglobulin (α₂-M), a plasma proteinase inhibitor, is a major component of these fluids. Since there have been reports describing the ability of α₂-M to form complexes with uPA in vitro, we hypothesized that α₂-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 α₂-M. Complexes between α₂-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 α₂-M retains its amidolytic activity towards low-molecularweight 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 α₂-M in vitro. We found that when α₂-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 α₂-M and that the effects may include the regulation of the fibrinolytic and signaling activities of uPA.