The extent of mast cell direct involvement in fibrosis is not defined as yet. In the present study we assessed whether long-term co-culture (up to 7 d) of functionally active rat peritoneal mast cells with 3T3 mouse fibroblasts and mass cell activation can affect fibroblast proliferation and collagen production. Co-culture of subconfluent 3T3 fibroblasts with resting mast cells or with mast cells stimulated by alpha IgE (1:35) or repeatedly activated by low concentrations of compound 48/80 (0.25-0.75 microgram/ml) did not alter fibroblast proliferation. However, fibroblast proliferation was increased significantly (100-130%) when mast cells were repeatedly activated with higher concentrations of compound 48/80 (1-3 micrograms/ml). Repeated mast cell activation by compound 48/80 (0.25 microgram/ml) caused a twofold increase in collagen production and this was reduced by 63% by the mast cell stabilizer nedocromil sodium (10(-5) M). At the same time, co-culture of 3T3 fibroblasts with unstimulated or immunologically activated mast cells did not modulate their collagen production. In conclusion, we have demonstrated that mast cell activation, under certain conditions, can enhance significantly 3T3 fibroblast proliferation and collagen production, thus indicating a direct mast cell involvement in the fibrotic processes.