Urokinase plasminogen activator released by alveolar epithelial cells modulates alveolar epithelial repair in vitro

Coretta Van Leer; Monika Stutz; André Haeberli; Thomas Geiser

doi:10.1160/TH05-03-0162

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2005; 94(06): 1257-1264
DOI: 10.1160/TH05-03-0162

Wound Healing and Inflammation/Infection

Schattauer GmbH

Urokinase plasminogen activator released by alveolar epithelial cells modulates alveolar epithelial repair in vitro

Authors

Coretta Van Leer

¹Division of Pulmonary Medicine

²Department of Clinical Research University Hospital, Bern, Switzerland
Monika Stutz

²Department of Clinical Research University Hospital, Bern, Switzerland
André Haeberli

²Department of Clinical Research University Hospital, Bern, Switzerland
Thomas Geiser

¹Division of Pulmonary Medicine

²Department of Clinical Research University Hospital, Bern, Switzerland

Abstract

Summary

Intra-alveolar fibrin is formed following lung injury and inflammation and may contribute to the development of pulmonary fibrosis. Fibrin turnover is altered in patients with pulmonary fibrosis, resulting in intra-alveolar fibrin accumulation, mainly due to decreased fibrinolysis. Alveolar type II epithelial cells (AEC) repair the injured alveolar epithelium by migrating over the provisional fibrin matrix. We hypothesized that repairing alveolar epithelial cells modulate the underlying fibrin matrix by release of fibrinolytic activity, and that the degree of fibrinolysis modulates alveolar epithelial repair on fibrin. To test this hypothesis we studied alveolar epithelial wound repair in vitro using a modified epithelial wound repair model with human A549 alveolar epithelial cells cultured on a fibrin matrix. In presence of the inflammatory cytokine interleukin-1β, wounds increase by 800% in 24 hours mainly due to detachment of the cells, whereas in serum-free medium wound areas decreases by 22.4 ± 5.2 % (p<0.01). Increased levels of D-dimer, FDP and uPA in the cell supernatant of IL-1β-stimulated A549 epithelial cells indicate activation of fibrinolysis by activation of the plasmin system. In presence of low concentrations of fibrinolysis inhibitors, including specific blocking anti-uPA antibodies, alveolar epithelial repair in vitro was improved, whereas in presence of high concentrations of fibrinolysis inhibitors, a decrease was observed mainly due to decreased spreading and migration of cells. These findings suggest the existence of a fibrinolytic optimum at which alveolar epithelial repair in vitro is most efficient. In conclusion, uPA released by AEC alters alveolar epithelial repair in vitro by modulating the underlying fibrin matrix.

Keywords

uPA - fibrin - alveolar epithelial repair - pulmonary fibrosis - fibrinolysis

Full Text

References

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