Induction of pulmonary fibrosis in organ-cultured rat lung by cadmium chloride and transforming growth factor- β1

Abstract

Cadmium chloride (CdCl 2) exposure has been reported to induce pulmonary fibrosis in rats. Accumulating evidence has shown that cytokines play a pivotal role in the excessive production of connective tissue components in pulmonary fibrosis. In this report, rat lung slice cultures were used to study the synergistic involvement of transforming growth factor- β1 (TGF- β1) in CdCl 2-induced alveolar fibrosis. Rat lung slices were maintained at the interphase of air and medium on a polyester mesh stretched on a plastic scaffold. Treatment of lung slices with 2.5, 5 or 10 μM CdCl 2 for 7 days resulted in 85, 40 and 6% respectively for relative survival. Under these culture conditions, CdCl 2 alone did not induce alveolar fibrosis in rat lung slices. However, in the presence of 0.5 ng/ml TGF- β1, CdCl 2 at a dose ranging from 1 to 5 μM increased the thickness of alveolar septa. Furthermore, the thickness of alveolar septa in lung slices treated with CdCl 2 was dose-dependently increased by the presence of TGF- β1. The thickened alveolar septa were apparently due to the deposition of excessive extracellular matrix, as revealed by trichrome stain and ultrastructural examination. Our results also show that fibrogenic activity induced by the combined treatment with CdCl 2 and TGF- β1 can be reduced by co-treatment with 200 μg/ml λ-carrageenan, a TGF- β1 inhibitor. Therefore, the present results indicate that TGF- β1 can synergistically stimulate the fibrogenic activity in lung tissue subsequent to CdCl 2 injury.