Novel aspects of urokinase function in the injured lung: Role of α2-macroglobulin

Andrey A. Komissarov, Dorota Stankowska, Agnieszka Krupa, Rafal Fudala, Galina Florova, Jon Florence, Marek Fol, Timothy C. Allen, Steven Idell, Michael A. Matthay, Anna K. Kurdowska

Research output: Contribution to journalArticle

9 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)L1037-L1045
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume303
Issue number12
DOIs
StatePublished - Dec 15 2012

Keywords

  • Epithelial cells
  • Inflammation
  • Lung
  • Urokinase
  • α-macroglobulin

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Fingerprint Dive into the research topics of 'Novel aspects of urokinase function in the injured lung: Role of α<sub>2</sub>-macroglobulin'. Together they form a unique fingerprint.

  • Cite this

    Komissarov, A. A., Stankowska, D., Krupa, A., Fudala, R., Florova, G., Florence, J., Fol, M., Allen, T. C., Idell, S., Matthay, M. A., & Kurdowska, A. K. (2012). Novel aspects of urokinase function in the injured lung: Role of α2-macroglobulin. American Journal of Physiology - Lung Cellular and Molecular Physiology, 303(12), L1037-L1045. https://doi.org/10.1152/ajplung.00117.2012