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.