To cause emphysema, proteases that are instilled into the air spaces must first be transported across the alveolar epithelium, a barrier that is normally quite impermeable to macromolecules. It was postulated that phospholipase A2 (PLA2) exposure would potentiate porcine pancreatic elastase (PPE)-induced epithelial solute permeability in a manner similar to that which was previously shown with lysophosphatidylcholine (lysoPC), a naturally occurring, membrane-pertubing agent that is formed principally through the hydrolysis of phosphatidylcholine by PLA2. Groups of hamsters were given intratracheal injections of PLA2 (0.3 units) or one of the expected hydrolytic products of PLA2 in equimolar concentrations, lysoPC (135 μg), arachidonic acid (AA) (100 μg), or palmitic acid (PA) (70 μg) with or without PPE (4 units). Epithelial permeability surface area products (PS) of the alveolar epithelium to [14C]sucrose and 125I-labeled neutral dextran (MW, 70,000) were measured in isolated perfused lungs 30 min after instillation, and emphysema severity was assessed at 3 wk by pressure-volume relationships and by mean linear intercepts. Additionally, the effects of lysoPC, PA, and AA on the functions of PPE and alpha1-antiprotease (α1-PI) in vitro were evaluated. Sucrose and dextran 70 PS differed significantly from controls only in those groups of hamsters that received PLA2, or lysoPC (p < 0.05). LysoPC and PLA2 also potentiated the severity of PPE-induced emphysema to a similar degree (p < 0.05). Neither AA nor PA affected epithelial solute permeability or emphysema severity at the doses administered. LysoPC, AA, and PA had no effect on hydrolysis of native elastin in vitro, but the three lipids exhibited an equal capability for impairing α1PI inhibition of PPE. These studies show that PLA2 augments PPE-induced emphysema, most likely through generation of lysoPC in situ, and consequent changes in alveolar epithelial permeability. Lysophosphatide and free fatty acid products of PLA2 activity are capable of inhibiting α1PI function, but this effect appears to be unimportant in this animal model.