Weibel and associates (Respir. Physiol. 18: 285-308, 1973), using morphometric techniques, demonstrated in the rat that changes in lung volume related to inflation and deflation caused a hysteretic variation in alveolar capillary membrane which is locally pleated at low pulmonary volume, unfolds during inflation but does not immediately refold during deflation, possibly enhancing the CO diffusion throughout the membrane. The present study was conducted to verify the existence of this hysteresis in human lungs in vivo. Single-breath diffusing capacity for CO (DLCO) was measured in five healthy seated subjects before and 0, 0.5, 1, 3, and 7 min after an inflation-deflation maneuver (IDM) in 6 separate days. The value of mean DLCO was 36.4 +/- 3 (SD) before and 42.1 +/- 2.9, 41.6 +/- 3.3, 40.3 +/- 3.3, 39.2 +/- 3.2, and 38.1 +/- 2.7 ml X min-1 X Torr-1 after the IDM. Two mechanisms can explain our findings: an active filling of the capillary bed, or an unfolding of the alveolar capillary membrane. The first mechanism should be accompanied by changes in pulmonary circulation. Therefore, right-heart catheterization was performed in two normal subjects and in four patients examined for a chest pain syndrome. At the end of the IDM, the values for the pulmonary artery pressure and capillary wedge pressure had returned to control levels. This suggests that the capillary bed is not directly involved in the DLCO increase observed from 0.5 to 7 min after the IDM. The unfolding of the alveolar capillary membrane appears to better explain our findings.(ABSTRACT TRUNCATED AT 250 WORDS)