Several investigators have shown that the clearance rate of aerosolized 99mTc-labeled diethylene triamine pentaacetate (DTPA, mol wt = 492, radius = 0.6 nm) from the air spaces of the lungs of humans and experimental animals increases with lung volume. To further investigate this phenomenon we peformed a compartmental analysis of the 2-h clearance of DTPA from the lungs of anesthetized sheep using a new method to more accurately correct for the effects of DTPA recirculation. This analysis showed that the DTPA clearance in eight sheep ventilated with zero end-expired pressure was best described by a one-compartment model with a clearance rate of 0.42 .+-. 0.15%/min. Ventilating eight sheep with an end-expired pressure of 10 cmH2O throughout the study increased the end-expired volume 0.4 .+-. 0.1 liter BTPS and created a clearance curve that was best described by a two-compartment model. In these sheep 56 .+-. 16% of the DTPA cleared from the lungs at a rate of 7.9 .+-. 2.9%/min. The remainder cleared at a rate similar to that measured in the sheep ventilated with zero end-expired pressure (0.35 .+-. 0.18%/min). Additional control and lung inflation experiments were performed using 99mTc-labeled human serum albumin (mol wet = 66,000, radius = 3.6 nm). In six control sheep ventilated with zero end-expired pressure the albumin clearance was best described by a one-compartment model with a clearance rate of 0.06 .+-. 0.02%/min. The clearance rate in six sheep with increased lung volume was slightly larger (0.09 .+-. 0.02, P < 0.05) but was well described by a one-compartment model. We conclude that lung inflation increases the size or number of 1- to 2-nm pores in only one anatomic area of the lungs (possibly the alveoli and terminal airways).