Goblet cell hyperplasia (GCH) is a frequent histologic finding in the airways of smokers. Experimental observations suggest that the process may be caused by increased proteinase activity in the airways. To investigate the possible role of cathepsin B in the development of GCH, male Syrian golden hamsters were given three intratracheal injections of bovine spleen cathepsin B or buffer (pH 5.5) at 2-day intervals. Six weeks later, we found by review of PAS-hematoxylin-stained 1-micron sections of plastic-embedded lung tissue that large intrapulmonary airways of animals given cathepsin B contained a significantly greater number of secretory cells per millimeter of airway (64.8 +/- 7.3 versus 47.5 +/- 10.3 for control animals, p less than 0.005) in association with a significant increase in the number of total cells per millimeter of airway, from 149 +/- 14 for control animals to 164 +/- 11 for cathepsin-B-treated animals (p less than 0.025). No change was observed in the number of ciliated cells (93.9 +/- 8.1/mm for control animals versus 94.8 +/- 10.3/mm for cathepsin-B-treated animals) or other cells (3.0 +/- 2.2/mm for control versus 4.3 +/- 4.1/mm for cathepsin B), indicating that selective expansion of the secretory cell population occurred. In contrast, in the main bronchi of animals given cathepsin B, no significant alterations were found in the number or percentage of secretory cells. The findings reveal that cathepsin B induces secretory cell hyperplasia in hamsters and suggest the possibility that cysteine proteinases may contribute to GCH in smokers.