Am. J. Respir. Crit. Care Med.,
Volume 157, Number 2, February 1998, 617-628
Role of Urokinase in the Fibrogenic Response of the
Lung to Mineral Particles
CÉCILE G.
LARDOT,
FRANÇOIS A.
HUAUX,
FABRICE R.
BROECKAERT,
PAUL J.
DECLERCK,
MONIQUE
DELOS,
BICE
FUBINI,
and
DOMINIQUE F.
LISON
Industrial Toxicology and Occupational Medicine Unit, Catholic University of Louvain, Brussels; Laboratory for Pharmaceutical Biology
and Phytopharmacology, Katholieke Universiteit Leuven, Leuven; Laboratory of Pathology, University Hospital of Mont Godinne,
Mont Godinne, Belgium; and Department of Inorganic, Physical and Materials Chemistry, University of Torino, Torino, Italy
The lung plasminogen activator (PA) response was examined in four different models of particle-
induced pulmonary lesions in NMRI mice (single intratracheal administration, 0.75 to 5 mg/mouse). Sequential changes in cellular (total and differential counts) and biochemical markers of alveolitis
(lactate dehydrogenase [LDH], total proteins) were monitored in bronchoalveolar fluid (BALF) and
the fibrotic lung response was assessed histologically. An intense but spontaneously resolving alveolitis was produced by manganese dioxide (MnO2) and a fibrosing alveolitis was elicited by crystalline
silica (DQ12). Minimal and noninflammatory responses were obtained after instillation of titanium dioxide (TiO2) and tungsten carbide (WC), respectively. The comparison between the resolving and the
fibrosing alveolitis model was especially taken into consideration in an attempt to identify fibrinolytic
changes associated with the development of fibrosis. At the alveolitis stage, similarly increased BALF
PA activities were measured in both the resolving and the fibrosing alveolitis models whereas only
slight and no PA modifications were noted after administration of TiO2 and WC, respectively. Persistently (up to 120 d) increased BALF PA activity was selectively associated with the progression to
fibrosis (DQ12), suggesting that PA is involved in the fibrotic process. ELISA measurements demonstrated that the changes in BALF PA activity were exclusively related to changes in urokinase (uPA), not tissue-type PA. A rapid and persisting (up to Day 30) upregulation of cell-associated PA activity
occurred after DQ12, MnO2, and TiO2 treatment only. Cellular PA activity was however significantly higher in fibrogenic inflammatory cells recovered from DQ12 than from MnO2-treated mice suggesting that the intensity of cellular PA upregulation may represent an early indicator of the progression to fibrosis. The implication of urokinase in the pathogenesis of silica-induced fibrosis was demonstrated by the use of a uPA knockout mice. The acceleration of the fibrotic process in uPA-deficient compared with the wild type animals demonstrated the contribution of uPA to limit the fibrotic process.
