Human Acinus Research Articles

The Motion and Deposition of Small Particles in the Human Lung Acinus, Part B: Weibel’s Model of Bifurcating Airways

Weibel’s model A for the human lung is applied in which the lung comprises a binary bifurcating tree of 23 generations of airways. It assumes that each airway bifurcates into two airways their sizes defined by the generation number. The goal of this analysis is to predict deposition efficiencies of various size particles which reach the human acinus vis-a-vis generation number, a result that can be used in designing inhaled therapeutical particles or preventing dangerous substances like Covid 19 of reaching the blood stream. The simulations account for particle convection, the effects of gravity and Brownian motion. Applying ANSYS Fluent, a commercial program which includes a two-phase model for finite volumes, it is found that particle diameters within the range (0.4 ¸ 1.0 mm) and densities as low as 500 kg/m3 reach deep into the human lung acinus and are likely to reach the blood stream. Particles of higher densities and diameters outside the foregoing range deposit at lower branches of the acinar tree, the smaller particles due to dominant diffusion and the bigger due to gravity.

Aerosol deposition in the pulmonary acinar region: Influence of wall motion and interparticle collisions

It is critical to accurately estimate the deposition of inhaled particles in the pulmonary acinus to reduce the damage of ambient aerosols or maximize drug particles' efficacy. However, interparticle interactions were always neglected in the simulation of aerosol deposition in human acinus. A four-generation human acinar model with varying sizes of each generation was developed. Two boundary conditions, rigid wall and moving wall were investigated to simulate the effect of wall motion on the flow field and aerosol deposition for the size range of 0.1–5 μm. Results show that wall motion has a net effect on particles' location and deposition, especially for submicron particles. Moreover, interparticle collisions were employed to gain richer aerosol particle dynamics. Results demonstrate that the minimum concentration of particles for coalescence is 8.5 × 104 particles/cm3 in the acinar region. The coalescence of particles is influenced by particle concentration and diameter, and wall motion and has a non-negligible effect on particle deposition. Furthermore, it should be noted that the influence of collision would be more significant during more respiratory cycles. Our findings demonstrate that wall motion and interparticle collisions play a non-negligible role in the aerosol deposition.

Investigation of tracer gas transport in a new numerical model of lung acini

Obstructive pulmonary diseases are associated with considerable morbidity. For an early diagnosis of these diseases, inert gas washouts can potentially be used. However, the complex interaction between lung anatomy and gas transport mechanisms complicates data analysis. In order to investigate this interaction, a numerical model, based on the finite difference method, consisting of two lung units connected in parallel, was developed to simulate the tracer gas transport within the human acinus. Firstly, the geometries of the units were varied and the diffusion coefficients (D) were kept constant. Secondly, D was changed and the geometry was kept constant. Furthermore, simple monoexponential growth functions were applied to evaluate the simulated data. In 109 of the 112 analyzed curves, monoexponential function matched simulated data with an accuracy of over 90%, potentially representing a suitable numerical tool to predict transport processes in further model extensions. For total flows greater than 5 × 10−4 ml/s, the exponential growth constants increased linearly with linear increasing flow to an accuracy of over 95%. The slopes of these linear trend lines of 1.23 µl−1 (D = 0.6 cm2/s), 1.69 µl−1 (D = 0.3 cm2/s), and 2.25 µl−1 (D = 0.1 cm2/s) indicated that gases with low D are more sensitive to changes in flows than gases with high D.Graphical abstract

Development of anatomically based structure for human acinus by Lindenmayer system: accurate model for gas exchange in human lung

Development of anatomically based structure for human acinus by Lindenmayer system: accurate model for gas exchange in human lung

Crystal structure of human Acinus RNA recognition motif domain.

Acinus is an abundant nuclear protein involved in apoptosis and splicing. It has been implicated in inducing apoptotic chromatin condensation and DNA fragmentation during programmed cell death. Acinus undergoes activation by proteolytic cleavage that produces a truncated p17 form that comprises only the RNA recognition motif (RRM) domain. We have determined the crystal structure of the human Acinus RRM domain (AcRRM) at 1.65 Å resolution. It shows a classical four-stranded antiparallel β-sheet fold with two flanking α-helices and an additional, non-classical α-helix at the C-terminus, which harbors the caspase-3 target sequence that is cleaved during Acinus activation. In the structure, the C-terminal α-helix partially occludes the potential ligand binding surface of the β-sheet and hypothetically shields it from non-sequence specific interactions with RNA. Based on the comparison with other RRM-RNA complex structures, it is likely that the C-terminal α-helix changes its conformation with respect to the RRM core in order to enable RNA binding by Acinus.

Simulation of Airflow in an Idealized Emphysematous Human Acinus.

Emphysema is the permanent enlargement of air spaces in the respiratory regions of the lung due to destruction of the inter-alveolar septa. The progressive coalescence of alveoli and alveolar ducts into larger airspaces leads to the disruption of normal airway wall motion and airflow rates within the pulmonary acinus. To contribute to the understanding of the individual effects of emphysema during its earliest stages, computational fluid dynamics (CFD) simulations of airflow in mathematically derived models of the pulmonary acinus were performed. The here generated computational domain consists of two generations of alveolar ducts within the pulmonary acinus, with alveolar geometries approximated as closely packed, 14-sided polygons. Physiologically realistic airflow rates and wall motions were used to study airflow patterns within subsequent generations of alveolar ducts during the inspiratory and expiratory phases of the breathing cycle. The effects of progressive emphysema on the airway wall motion and flow rates were simulated by sequentially removing all alveolar septa within each alveolar duct. Parametric studies were presented to independently assess the relative influence of progressive septal destruction of airway motion and flow rates. The results illustrate that septal destruction lowers the flow resistance through the alveolar ducts but has little influence on the mass transport of oxygen into the alveoli. Septal destruction has a net effect on the flow field by favoring the development of recirculatory flow patterns in individual alveoli.

Airflow patterns in a 3D model of the human acinus

Based on the recent photographs of microstructures of anacinus a novel 3D computational model for airflow and particle transport and deposition was developed. To model the entireacinar region simultaneously, an approach was proposed to reduce the computational space. The airflow was solved using numerical simulations for the cases of expanding and contracting the asinus wall. The volume change of the lung was imposed based on the normal breathing condition with 15% volumetric expansion ratio. Since the entire acinar region was modeled, realistic pressure type boundary conditions were used and the use of earlier unrealistic boundary conditions was avoided. The simulation results showed that the flow patterns in an acinus with moving walls were significantly different from those for the rigid wall case. Furthermore, due to the asymmetric configuration, the flow patterns were not quite symmetric. It was shown that the ratio of alveolar flow to ductal flow rate controlled the dominant flow regime in each generation. Ratios below 0.005led to recirculation regime where flow separation occurred, while values above this threshold led to flows with radial streamlines. In summary, while the flow in the primary generations was characterized by the formation of recirculation regions in the alveoli, the terminal generations were characterized by radial streamlines which move towards the alveolar wall. Both flow regimes had substantial effects on particle deposition in the acinus.

Onset of alveolar recirculation in the developing lungs and its consequence on nanoparticle deposition in the pulmonary acinus.

The structure of the gas exchange region of the human lung (the pulmonary acinus) undergoes profound change in the first few years of life. In this paper, we investigate numerically how the change in alveolar shape with time affects the rate of nanoparticle deposition deep in the lung during postnatal development. As human infant data is unavailable, we use a rat model of lung development. The process of postnatal lung development in the rat is remarkably similar to that of the human, and the structure of the rat acinus is indistinguishable from that of the human acinus. The current numerical predictions support our group's recent in vivo findings, which were also obtained by using growing rat lung models, that nanoparticle deposition in infants is strongly affected by the change in the structure of the pulmonary acinus. In humans, this major structural change occurs over the first 2 yr of life. Our current predictions would suggest that human infants at the age of ∼ 2 yr might be most at risk to the harmful effects of air pollution. Our results also suggest that dose estimates for inhalation therapies using nanoparticles, based on fully developed adult lungs with simple body weight scaling, are likely to overestimate deposition by up to 55% for newborns and underestimate deposition by up to 17% for 2-yr-old infants.

Synchrotron-based Micro-CT Imaging of the Human Lung Acinus

Aim: Structural data about the human lung fine structure are mainly based on stereological methods applied to serial sections. The purpose of our study was to generate a complete data set of the intact 3-dimensional architecture of the human acinus using high-resolution synchrotron-based micro-CT (synMCT).

Synchrotron‐Based Micro‐CT Imaging of the Human Lung Acinus

Structural data about the human lung fine structure are mainly based on stereological methods applied to serial sections. As these methods utilize 2D images, which are often not contiguous, they suffer from inaccuracies which are overcome by analysis of 3D micro-CT images of the never-sectioned specimen. The purpose of our study was to generate a complete data set of the intact three-dimensional architecture of the human acinus using high-resolution synchrotron-based micro-CT (synMCT). A human lung was inflation-fixed by formaldehyde ventilation and then scanned in a 64-slice CT over its apex to base extent. Lung samples (8-mm diameter, 10-mm height, N = 12) were punched out, stained with osmium tetroxide, and scanned using synMCT at (4 μm)(3) voxel size. The lung functional unit (acinus, N = 8) was segmented from the 3D tomographic image using an automated tree-analysis software program. Morphometric data of the lung were analyzed by ANOVA. Intra-acinar airways branching occurred over 11 generations. The mean acinar volume was 131.3 ± 29.2 mm(3) (range, 92.5-171.3 mm(3)) and the mean acinar surface was calculated with 1012 ± 26 cm(2). The airway internal diameter (starting from the bronchiolus terminalis) decreases distally from 0.66 ± 0.04 mm to 0.34 ± 0.06 mm (P < 0.001) and remains constant after the seventh generation (P < 0.5). The length of each generation ranges between 0.52 and 0.93 mm and did not show significant differences between the second and eleventh generation. The branching angle between daughter branches varies between 113-degree and 134-degree without significant differences between the generations (P < 0.3). This study demonstrates the feasibility of quantitating the 3D structure of the human acinus at the spatial resolution readily achievable using synMCT.

Acinar determinants of the apparent diffusion coefficient for helium-3

The apparent diffusion coefficient (ADC) obtained by helium-3 magnetic resonance imaging over several seconds is thought to reflect diffusion impairment due to both intra- and interacinar structure. In this study, numerical simulations of intra-acinar gas mixing and effective diffusion were performed in a multiple-branch-point model of the human acinus. Using a previously described method, we computed the instantaneous effective diffusion resulting from the diffusive impairment imposed by intra-acinar branching for varying times up to 5 s. We also tested the influence on effective diffusion of intra-acinar collateral channels in the fully alveolated intra-acinar airways to mimic the effect of emphysema. Randomly connecting two or four pairs of airways per generation (in generations 19-25) led to a 40 and 142% increase, respectively, in effective diffusion coefficient cumulated over the time interval of 0.2-5 s. Finally, we also used a system of two coupled multiple branch-point models to simulate diffusive attenuation over a 50-s interval in cases of purely acinar tagging (i.e., the initial gas concentration = 1 in one acinus and 0 in the other) and of partial tagging astride on two acini. It is shown that, in the latter case, the decay rate cannot be approximated by a mono-exponential with a several-fold faster decay for times below 10 s due to intra-acinar diffusion. We conclude that both the characteristic biphasic time dependence of simulated effective diffusion and its sensitivity to intra-acinar structural change mimic experimental ADC behavior. Additional simulations of combined inter- and intra-acinar diffusion strongly suggest that neglecting intra-acinar branching would in fact lead to considerable error of simulated ADC.

Diffusion of gases into the lung: How physics can help to understand physiology

In the human lung, the gas transfer between air and blood is achieved in terminal units that are called ‘acini’. Whereas convection is still the predominant transport phenomenon at the acinus entrance, most of the acinar surface is in fact accessed by diffusion. The transition between convection and diffusion, and thus the size of the diffusion unit, depends on the air velocity at the acinus entrance. In this paper, we present a gas transport model which takes into account both the diffusion into the acinus and the diffusion across the alveolar membrane. It is shown that the physiological sizes of the diffusion unit in the lung, at rest or at exercise, can be explained by physical arguments. In that sense, diffusion is the ‘dimensioning criterion’ of the lung at the acinar level. This approach shows that, due to diffusional screening at inspiration and at rest, there exists a permanent spatial inhomogeneity of oxygen and carbon dioxide partial pressure which reduces the effective surface efficiency of the human acinus to a value of only 30 to 40%. This model casts a new light on the properties of this physiological transport system. It permits in particular to understand how several diseases among which pulmonary edema may remain asymptomatic in their early stages.

Gas diffusion in a pulmonary acinus model: experiments with hyperpolarized helium-3

Diffusion of hyperpolarized helium-3 in epoxy phantoms was experimentally studied by pulsed-gradient nuclear magnetic resonance (NMR). One phantom with a dichotomic branching structure densely filling a cubic volume was built using the Kitaoka algorithm to model a healthy human acinus. Two other phantoms, one with a different size and the other one with a partial destruction of the branched structure, were built to simulate changes occurring at the early stages of emphysema. Gas pressure and composition (mixture with nitrogen) were varied, thus exploring different diffusion regimes. Preliminary measurements in a cylindrical glass cell allowed us to calibrate the gradient intensity with 1% accuracy. Measurements of NMR signal attenuation due to gas diffusion were compared to a classical Gaussian model and to Monte Carlo simulations. In the slow diffusion regime, the Gaussian model was in reasonable agreement with experiments for low gradient intensity, but there was a significant systematic deviation at larger gradient intensity. An apparent diffusion coefficient Dapp was deduced, and in agreement with previous findings, a linear decrease of Dapp/D0 with D0(1/2) was observed, where D0 is the free diffusion coefficient. In the regime of intermediate diffusion, experimental data could be described by the Gaussian model for very small gradient intensities only. The corresponding Dapp/D0 values seemed to reach a constant value. Monte Carlo simulations were generally in fair agreement with the measurements in both regimes. Our results suggest that, for diffusion times typical of medical magnetic resonance imaging, an increase in alveolar size has more impact on signal attenuation than a partial destruction of the branched structure at equivalent surface-to-volume ratio.

Simulation of the apparent diffusion of helium-3 in the human acinus

Functional MRI of the lungs with hyperpolarized helium provides an index of apparent diffusion measured over several seconds (ADCsec) that is only 2% of its free diffusion in air (0.88 cm2/s). The potential of ADCsec to noninvasively assess in vivo lung structure of diseased lungs at the length scales corresponding to several seconds is critically dependent on the exact link between ADCsec and lung peripheral structure. To understand the intruigingly small ADCsec, numerical simulations of gas transport were performed in 1) a trumpet model, 2) a symmetrical, and 3) an asymmetrical multiple-branch-point model of the human acinus. For initial gas boluses in different locations of the acinar models, ADCsec was quantified as follows. At different time intervals, we computed a coefficient of variation (CoV) of the concentration distributions within each acinar model. The slope in the semilog plot of log(CoV) vs. time was proportional to the ADCsec generated by the internal model structure, provided that the outer model boundaries were similar across all models (i.e., similar cumulative cross section vs. average path length). The simulations revealed an ADCsec that amounted to approximately 1% of free diffusion in the trumpet model of the acinus, i.e., corresponding to free diffusion within the acinar geometric boundaries. Our simulations show that for initial conditions corresponding to those used in MRI experiments, intra-acinar branching introduces a dramatic diffusion delay, comparable to what is observed experimentally.

Renormalized random walk study of oxygen absorption in the human lung

Gas exchange at the acinar level involves several physico-chemical phenomena within a complex geometry. A gas transport model, which takes into account both the diffusion into the acinus and the diffusion across the alveolar membrane, is used to understand gas mixing in realistic systems. The behaviour of the system, first computed on model geometries in 3D finite elements method, can in fact be derived from the topological structure of the acinus only. A new efficient method based on random walks on a lattice is thus used to compute gas diffusion in structures taken from real morphological data. This approach shows that, at rest, the human acinus efficiency is only of 30–40%. These results provide a new evidence of the existence of diffusional screening at the acinar level, which means permanent spatial inhomogeneity of oxygen and carbon dioxide partial pressure. Application of these results to CO 2 clearance provides for the first time a theoretical support to the empirical relation between the O 2 and CO 2 partial pressures.

Diffusional screening in real 3D human acini—a theoretical study

Gas exchange at the acinar level involves several physico-chemical phenomena within a complex geometry. A gas transport model, which takes into account both the diffusion into the acinus and the diffusion across the alveolar membrane, is used to understand gas mixing in realistic systems. It is first shown that the behaviour of the system, computed on model geometries in 3D, only depends on the topological structure of the acinus. Taking advantage of this property, a new efficient method based on random walks on a lattice is used to compute gas diffusion in structures taken from real morphological data. This approach shows that, at rest, the human acinus efficiency is only 30-40%. These results provide a new evidence of the existence of diffusional screening at the acinar level. This implies permanent spatial inhomogeneity of oxygen and carbon dioxide partial pressure. The notion of an "alveolar gas" is reinterpreted as a spatial average of the gas distribution. This model casts new light on the respiratory properties of other gas mixtures, such as helium-oxygen.

Renormalized random walk study of oxygen absorption in the human lung.

The possibility to renormalize random walks is used to study numerically the oxygen diffusion and permeation in the acinus, the diffusion cell terminating the mammalian airway tree. This is done in a 3D tree structure which can be studied from its topology only. The method is applied to the human acinus real morphology as studied by Haefeli-Bleuer and Weibel in order to compute the respiratory efficiency of the human lung. It provides the first quantitative evidence of the role of diffusion screening in real 3D mammalian respiration. The net result of this study is that, at rest, the efficiency of the human acinus is only of order 33%. Application of these results to CO2 clearance provides for the first time a theoretical support to the empirical relation between the O2 and CO2 partial pressures in blood.

Effect of gravitational sedimentation on simulated aerosol dispersion in the human acinus

We studied the effect of gravitational sedimentation on the dispersion of 0.5 and 1 μm -diameter particle boluses within a two-dimensional symmetric six-generation model of the human acinus. Boluses were introduced at the beginning of a 2-s inspiration immediately followed by a 4-s expiration, in normal gravity (1G) and in the absence of gravity (0G). The flow corresponded to a flow rate at the mouth of 500 ml/ s . In 0G, simulated dispersion ( H sim) was 16 ml for both particle sizes. In 1G, H sim was 71 and 242 ml for 0.5 and 1 μm -diameter particles, respectively, showing the effect of gravitational sedimentation. The difference between experimental data (J. Appl. Physiol. 86 (1999) 1402) and simulations was independent of particle size. This suggests that the residual dispersion was independent of the intrinsic properties of the particles and was more likely due to other mechanisms such as ventilation inhomogeneities, cardiogenic oscillations and alveolar wall motion.

Heterogeneity of aerosol deposition in a two-dimensional model of human alveolated ducts

Transport of 0.5– 5 μm diameter particles was simulated within a symmetric two-dimensional (2D) six-generation structure representative of the human acinus. Aerosol boluses were introduced at the beginning of a breathing cycle (2-s inspiration, 2-s expiration). Airflow corresponded to a flow rate at the mouth of 500 ml/s . Deposition increased from 1% to 100% for 0.5– 5 μm diameter particles. Deposition agreed with the upper limit of alveolar deposition predicted by the one-dimensional (1D) ICRP66 model but only after accounting for multibreath. The 2D model showed that, for each particle size and structure orientation, there was a large heterogeneity in deposition among ducts. Differences of more than one order of magnitude were found between deposition in a single duct of a given generation and the average deposition in that generation. The presence of “hot spots” may have important implications in human health as several studies suggest a strong correlation between airborne pollutants and the onset of pulmonary or cardiovascular diseases.

A human acinar structure for simulation of realistic alveolar plateau slopes.

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.