Neutrophils contribute to inflammatory injury in some types of acute and chronic lung disease. Among the injurious agents released by activated neutrophils are cationic proteins such as cathepsin G that may contribute to edema formation. Using cultured rat type II alveolar epithelium, we examined the effect of human neutrophil cathepsin G on permeability to mannitol and electrical resistance across the cultured epithelium. Monolayers maintained in control media alone had constant permeability to mannitol (4.5 +/- 0.3 X 10(-3) cm/h at base line and 4.4 +/- 0.3 X 10(-3) cm/h after 2 h). When monolayers were exposed to cathepsin G at concentrations of 5, 10, and 20 micrograms/ml, there was a progressive increase in mannitol permeability (120 +/- 26% increase at 5 micrograms/ml, 174 +/- 40% increase at 10 micrograms/ml and 301 + 116% increase at 20 micrograms/ml, P less than 0.001). The effect of cathepsin G on mannitol permeability was blocked by the presence of the polyanion-sulfated dextran, and the polycation protamine also increased permeability to mannitol 57 +/- 5% (P less than 0.001), suggesting a role for charge in this effect. Cathepsin G exposure also resulted in a progressive decrease in electrical resistance (67 +/- 2% base line after 15 min, 55 +/- 1% after 30 min, and 43 +/- 2% after 60 min). Cathepsin G at these concentrations was not cytolytic to the cells as measured by lactate dedrogenase release. These functional alterations were accompanied by increase in intercellular gaps in the monolayers seen on scanning electron microscopy.(ABSTRACT TRUNCATED AT 250 WORDS)