We simulated the intra-acinar contribution to phase III slope (S(acin)) for gases of differing diffusivities (He and SF(6)) by solving equations of diffusive and convective gas transport in multi-branch-point models (MBPM) of the human acinus. We first conducted a sensitivity study of S(acin) to asymmetry and its variability in successive generations. S(acin) increases were greatest when asymmetry and variability of asymmetry were increased at the level of the respiratory bronchioles (generations 17-18) for He and at the level of the alveolar ducts (generations 20-21) for SF(6), corresponding to the location of their respective diffusion fronts. On the basis of this sensitivity study and in keeping with reported acinar morphometry, we built a MBPM that actually reproduced experimental S(acin) values obtained in normal subjects for He, N(2), and SF(6). Ten variants of such a MBPM were constructed to estimate intrinsic S(acin) variability owing to peripheral lung structure. The realistic simulation of S(acin) in the normal lung and the understanding of how asymmetry affects S(acin) for different diffusivity gases make S(acin) a powerful tool to detect structural alterations at different depths in the lung periphery.

We performed single-breath washout (SBW) tests in which He and sulfur hexafluoride (SF6) were inspired throughout the vital capacity inspirations or were inhaled as discrete boluses at different points in the inspiration. Tests were performed in normal gravity (1 G) and in up to 27 s of microgravity (microG) during parabolic flight. The phase III slope of the SBW could be accurately reconstructed from individual bolus tests when allowance for airways closure was made. Bolus tests showed that most of the SBW phase III slope results from events during inspiration at lung volumes below closing capacity and near total lung capacity, as does the SF6-He phase III slope difference. Similarly, the difference between 1 G and microG in phase III slopes for both gases was entirely accounted for by gravity-dependent events at high and low lung volumes. Phase IV height was always larger for SF6 than for He, suggesting at least some airway closure in close proximity to airways that remain open at residual volume. These results help explain previous studies in microG, which show large changes in gas mixing in vital capacity maneuvers but only small effects in tidal volume breaths.

We performed tidal volume single-breath washins (SBW) by using tracers of different diffusivity and varied the time spent in microgravity (microG) before the start of the tests to look for time-dependent effects. SF(6) and CH(4) phase III slopes decreased by 35 and 26%, respectively, in microG compared with 1 G (P < 0.05), and the slope difference between gases disappeared. There was no effect of time in microG, suggesting that neither the hypergravity period preceding microG nor the time spent in microG affected gas mixing at volumes near functional residual capacity. In previous studies using SF(6) and He (Lauzon A-M, Prisk GK, Elliott AR, Verbanck S, Paiva M, and West JB. J Appl Physiol 82: 859-865, 1997), the vital capacity SBW showed an increase in slope difference between gases in transient microG, the opposite of the decrease in sustained microG. In contrast, tidal volume SBW showed a decrease in slope difference in both microG conditions. Because it is only the behavior of the more diffusive gas that differed between maneuvers and microG conditions, we speculate that, in the previous vital capacity SBW, the hypergravity period preceding the test in transient microG provoked conformational changes at low lung volumes near the acinar entrance.

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