INDUCTION OF PULMONARY FIBROSIS IN ORGAN-CULTURED RAT LUNG BY CADMIUMCHLORIDE AND TRANSFORMING GROWTH-FACTOR-BETA-1

Cadmium chloride (CdCl2) exposure has been reported to induce pulmonar y fibrosis in rats. Accumulating evidence has shown that cytokines pla y a pivotal role in the excessive production of connective tissue comp onents in pulmonary fibrosis. In this report, rat lung slice cultures were used to study the synergistic involvement of transforming growth factor-beta 1 (TGF-beta 1) in CdCl2-induced alveolar fibrosis. Rat lun g slices were maintained at the interphase of air and medium on a poly ester mesh stretched on a plastic scaffold. Treatment of lung slices w ith 2.5, 5 or 10 mu M CdCl2 for 7 days resulted in 85, 40 and 6% respe ctively for relative survival. Under these culture conditions, CdCl2 a lone did not induce alveolar fibrosis in rat lung slices. However, in the presence of 0.5 ng/ml TGF-beta 1, CdCl2 at a dose ranging from 1 t o 5 mu M increased the thickness of alveolar septa. Furthermore, the t hickness of alveolar septa in lung slices treated with CdCl2 was dose- dependently increased by the presence of TGF-beta 1. The thickened alv eolar septa were apparently due to the deposition of excessive extrace llular matrix, as revealed by trichrome stain and ultrastructural exam ination. Our results also show that fibrogenic activity induced by the combined treatment with CdCl2 and TGF-beta 1 can be reduced by co-tre atment with 200 mu g/ml lambda-carrageenan, a TGF-beta 1 inhibitor. Th erefore, the present results indicate that TGF-P 1 can synergistically stimulate the fibrogenic activity in lung tissue subsequent to CdCl2, injury. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.