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 Citations (Scopus)

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)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume303
Issue number12
DOIs
StatePublished - Dec 15 2012
Externally publishedYes

Fingerprint

Macroglobulins
Acute Lung Injury
Adult Respiratory Distress Syndrome
Urokinase-Type Plasminogen Activator
Lung
Epithelial Cells
Complement Factor B
Plasminogen Activator Inhibitor 1
Pulmonary Edema
Interleukin-8
Interleukin-6
Edema
Peptide Hydrolases
In Vitro Techniques

Keywords

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

ASJC Scopus subject areas

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

Cite this

Novel aspects of urokinase function in the injured lung : Role of α2-macroglobulin. / Komissarov, Andrey A.; Stankowska, Dorota; Krupa, Agnieszka; Fudala, Rafal; Florova, Galina; Florence, Jon; Fol, Marek; Allen, Timothy C.; Idell, Steven; Matthay, Michael A.; Kurdowska, Anna K.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 303, No. 12, 15.12.2012.

Research output: Contribution to journalArticle

Komissarov, AA, Stankowska, D, Krupa, A, Fudala, R, Florova, G, Florence, J, Fol, M, Allen, TC, Idell, S, Matthay, MA & Kurdowska, AK 2012, 'Novel aspects of urokinase function in the injured lung: Role of α2-macroglobulin', American Journal of Physiology - Lung Cellular and Molecular Physiology, vol. 303, no. 12. https://doi.org/10.1152/ajplung.00117.2012
Komissarov, Andrey A. ; Stankowska, Dorota ; Krupa, Agnieszka ; Fudala, Rafal ; Florova, Galina ; Florence, Jon ; Fol, Marek ; Allen, Timothy C. ; Idell, Steven ; Matthay, Michael A. ; Kurdowska, Anna K. / Novel aspects of urokinase function in the injured lung : Role of α2-macroglobulin. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2012 ; Vol. 303, No. 12.
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