We administered low dose porcine pancreatic elastase (PPE) with and without lysophosphatidylcholine (lysoPC), a naturally occurring constituent of lung lipids with known membrane-perturbing properties, to test the hypothesis that alveolar epithelial solute permeability is a determinant of the severity of elastase-induced emphysema in experimental animals. Four age- and weight-matched groups of hamsters received intratracheal injections of one of the following in a total volume of 0.5 ml TRIS buffered saline: (1) no additions, (2) 4 units PPE, (3) 135 μg lysoPC, or (4) 4 units PPE plus 135 μg lysoPC. Thirty minutes later the permeability surface area products (PS) of the alveolar epithelium to 14C-sucrose and 125I-dextran 70 were measured in excised, perfused lungs from some animals from each group. The remaining animals were killed at 6 wk, at which time pressure-volume relationships were measured in excised lungs, and the mean linear intercept was determined from sections of fixed lung tissue. Neither PPE nor lysoPC alone caused statistically significant increases in PS for either tracer. The PPE plus lysoPC caused statistically insignificant increases in sucrose PS but approximate tenfold increases in dextran 70 PS, which were highly significant (p < 0.001). Although focal air-space enlargement was observed in some lungs 6 wk after exposure to PPE, pressure-volume relationships and mean linear intercepts were not significantly different from control values. Lung previously exposed to lysoPC were indistinguishable from control lungs for all measurements. Severe emphysema was uniformly observed in animals that received PPE in combination with lysoPC; lysoPC had no demonstrable effect upon PPE-induced hydrolysis of native elastin in vitro. These studies show that lysoPC amplifies PPE-induced emphysema, most likely by enhancing epithelial permeability to macromolecular elastase.