The study examined how lung hyaluronic acid content influences airspace enlargement in elastase-induced emphysema. To determine the effect of a decrease in hyaluronic acid, hamsters received a single intratracheal instillment of hyaluronidase 24 h prior to administration of pancreatic elastase by the same route. One week later, these animals showed significantly greater airspace enlargement than controls sequentially instilled with saline and elastase (128 vs. 100 microns; p < .05). Conversely, intratracheal administration of hyaluronic acid immediately after elastase instillment resulted in a marked decrease in airspace enlargement at 1 week compared to controls receiving elastase followed by saline (82 vs. 122 microns; p = .005). Since hyaluronic acid has no elastase inhibitory capacity, its effect may involve extracellular matrix interactions not directly related to elastic fiber breakdown. This concept is supported by the finding that animals treated with hyaluronidase and elastase showed no greater loss of lung elastin than that observed in the saline/elastase control group, despite demonstrating a marked increase in airspace enlargement. Further work is needed to determine how hyaluronic acid influences airspace enlargement and to evaluate the potential use of this substance as a treatment for emphysema.