Obstructions in the lower airways lead to altered airflow patterns in the central airway.

A characteristic feature of obstructive lung diseases is the narrowing of small airways, which affects regional airflow patterns within the lung. However, the extent to which these patterns differ between healthy and diseased states is unknown. To investigate airflow patterns in detail, we first used particle image velocimetry measurements to validate a large eddy simulation model of flow in a patient-specific geometry. We then predicted flow patterns in the central airway under exhalation for three flow conditions-normal, intermediate, and severe-where boundary conditions represented the effect of lower airway obstructions. We computed Pearson correlation coefficients (R) to assess the similarity of flow patterns, and found that flow patterns demonstrated the greatest differentiation between flow conditions in the right main bronchi (R ≤0.60), whereas those in the secondary branches and regions of the trachea showed high correlation (R ≥0.90). These results indicate that although flow patterns are distinct between flow conditions, the choice of measurement location is critical for differentiation.

Volumetric characteristics of idiopathic pulmonary fibrosis lungs: computational analyses of high-resolution computed tomography images of lung lobes.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease involving progressive degeneration of lung capacity. Current diagnosis of IPF heavily relies on visual evaluation of fibrotic features in high-resolution computed tomography (HRCT) images of the lungs. Although the characteristics of this disease have been studied at the molecular and cellular levels, little is known about the mechanical characteristics of IPF lungs inferred from HRCT images. To this end, we performed a pilot study to investigate the radiographic and volumetric characteristics of lungs in subjects with IPF. METHODS: We collected HRCT images of healthy (N = 13) and IPF (N = 9) lungs acquired at breath-holds after full inspiration (expanded state) and full expiration (contracted state). We performed statistical analyses on Hounsfield unit (HU) histograms, lobar volumes (V: lobe volume normalized by the lung volume), and lobar flows (Q: the difference in lobe volume divided by the difference in lung volume between the expanded and contracted states). RESULTS: Parameters characterizing the HU histograms (i.e., mean, median, skewness, and kurtosis) significantly differed between healthy and IPF subjects, for all lobes in both expanded and contracted states. The distribution of V across lobes differed significantly between the groups in both states. The distribution of Q also differed significantly between the groups: Q values of the lower lobes for the IPF group were 33% (right) and 22% (left) smaller than those for the healthy group, consistent with the observation that radiographic scores were highest in the lower lung section in IPF. Notably, the root-mean-squared difference (RMSD) of Q, a measure of distance from the mean value of the healthy group, clearly distinguished the IPF subjects (RMSD of Q > 1.59) from the healthy group (RMSD of Q < 0.67). CONCLUSION: This study shows that lung volume and flow distribution change heterogeneously across the lung lobes of IPF subjects, with reduced capacity in the lower lobes. These volumetric changes may improve our understanding of the pathophysiology in IPF lungs.

Dynamics of the Tracheal Airway and Its Influences on Respiratory Airflows: An Exemplar Study.

Respiration is a dynamic process accompanied by morphological changes in the airways. Although deformation of large airways is expected to exacerbate pulmonary disease symptoms by obstructing airflow during increased minute ventilation, its quantitative effects on airflow characteristics remain unclear. Here, we used in vivo dynamic imaging and examined the effects of tracheal deformation on airflow characteristics under different conditions based on imaging data from a single healthy volunteer. First, we measured tracheal deformation profiles of a healthy lung using magnetic resonance imaging (MRI) during forced exhalation, which we simulated to characterize the subject-specific airflow patterns. Subsequently, for both inhalation and exhalation, we compared the airflows when the modeled deformation in tracheal cross-sectional area was 0% (rigid), 33% (mild), 50% (moderate), or 75% (severe). We quantified differences in airflow patterns between deformable and rigid airways by computing the correlation coefficients (R) and the root-mean-square of differences (Drms) between their velocity contours. For both inhalation and exhalation, airflow patterns were similar in all branches between the rigid and mild conditions (R > 0.9; Drms < 32%). However, airflow characteristics in the moderate and severe conditions differed markedly from those in the rigid and mild conditions in all lung branches, particularly for inhalation (moderate: R > 0.1, Drms < 76%; severe: R > 0.2, Drms < 96%). Our exemplar study supports the use of a rigid airway assumption to compute flows for mild deformation. For moderate or severe deformation, however, dynamic contraction should be considered, especially during inhalation, to accurately predict airflow and elucidate the underlying pulmonary pathology.

Assessing Airflow Sensitivity to Healthy and Diseased Lung Conditions in a Computational Fluid Dynamics Model Validated In Vitro.

Computational models are useful for understanding respiratory physiology. Crucial to such models are the boundary conditions specifying the flow conditions at truncated airway branches (terminal flow rates). However, most studies make assumptions about these values, which are difficult to obtain in vivo. We developed a computational fluid dynamics (CFD) model of airflows for steady expiration to investigate how terminal flows affect airflow patterns in respiratory airways. First, we measured in vitro airflow patterns in a physical airway model, using particle image velocimetry (PIV). The measured and computed airflow patterns agreed well, validating our CFD model. Next, we used the lobar flow fractions from a healthy or chronic obstructive pulmonary disease (COPD) subject as constraints to derive different terminal flow rates (i.e., three healthy and one COPD) and computed the corresponding airflow patterns in the same geometry. To assess airflow sensitivity to the boundary conditions, we used the correlation coefficient of the shape similarity (R) and the root-mean-square of the velocity magnitude difference (Drms) between two velocity contours. Airflow patterns in the central airways were similar across healthy conditions (minimum R, 0.80) despite variations in terminal flow rates but markedly different for COPD (minimum R, 0.26; maximum Drms, ten times that of healthy cases). In contrast, those in the upper airway were similar for all cases. Our findings quantify how variability in terminal and lobar flows contributes to airflow patterns in respiratory airways. They highlight the importance of using lobar flow fractions to examine physiologically relevant airflow characteristics.

A computational study of the respiratory airflow characteristics in normal and obstructed human airways.

Obstructive lung diseases in the lower airways are a leading health concern worldwide. To improve our understanding of the pathophysiology of lower airways, we studied airflow characteristics in the lung between the 8th and the 14th generations using a three-dimensional computational fluid dynamics model, where we compared normal and obstructed airways for a range of breathing conditions. We employed a novel technique based on computing the Pearson׳s correlation coefficient to quantitatively characterize the differences in airflow patterns between the normal and obstructed airways. We found that the airflow patterns demonstrated clear differences between normal and diseased conditions for high expiratory flow rates (>2300ml/s), but not for inspiratory flow rates. Moreover, airflow patterns subjected to filtering demonstrated higher sensitivity than airway resistance for differentiating normal and diseased conditions. Further, we showed that wall shear stresses were not only dependent on breathing rates, but also on the distribution of the obstructed sites in the lung: for the same degree of obstruction and breathing rate, we observed as much as two-fold differences in shear stresses. In contrast to previous studies that suggest increased wall shear stress due to obstructions as a possible damage mechanism for small airways, our model demonstrated that for flow rates corresponding to heavy activities, the wall shear stress in both normal and obstructed airways was <0.3Pa, which is within the physiological limit needed to promote respiratory defense mechanisms. In summary, our model enables the study of airflow characteristics that may be impractical to assess experimentally.

Gating of two mechanoelectrical transducer channels associated with a single tip link.

Although gating of mechanoelectrical transducer (MET) channels has been successfully described by assuming that one channel is associated with a tip link in the hair bundle, recent reports indicate that a single tip link is associated with more than one channel. To address the consistency of the model with the observations, gating of MET channels is described here by assuming that each tip link is associated with two identical MET channels, which are connected either in series or in parallel. We found that series connection does not lead to a single minimum of stiffness with respect to hair bundle displacement unless the minimum is above a certain positive value. Thus, negative stiffness must appear in pairs in the displacement axis. In contrast, parallel connection of the two channels predicts gating compliance similar to that predicted by the one-channel-per-tip-link model of channel gating, within the physiological range of parameters. Parallel connection of MET channels is, therefore, a reasonable assumption to explain most experimental observations. However, the compatibility with series connection cannot be ruled out for experimental data on turtle hair cells.

Effectiveness of hair bundle motility as the cochlear amplifier.

The effectiveness of hair bundle motility in mammalian and avian ears is studied by examining energy balance for a small sinusoidal displacement of the hair bundle. The condition that the energy generated by a hair bundle must be greater than energy loss due to the shear in the subtectorial gap per hair bundle leads to a limiting frequency that can be supported by hair-bundle motility. Limiting frequencies are obtained for two motile mechanisms for fast adaptation, the channel re-closure model and a model that assumes that fast adaptation is an interplay between gating of the channel and the myosin motor. The limiting frequency obtained for each of these models is an increasing function of a factor that is determined by the morphology of hair bundles and the cochlea. Primarily due to the higher density of hair cells in the avian inner ear, this factor is approximately 10-fold greater for the avian ear than the mammalian ear, which has much higher auditory frequency limit. This result is consistent with a much greater significance of hair bundle motility in the avian ear than that in the mammalian ear.

Amplifying effect of a release mechanism for fast adaptation in the hair bundle.

A "release" mechanism, which has been experimentally observed as the fast component in the hair bundle's response to mechanical stimulation, appears similar to common mechanical relaxation with a damping effect. This observation is puzzling because such a response is expected to have an amplifying role in the mechanoelectrical transduction process in hair cells. Here it is shown that a release mechanism can indeed have a role in amplification, if it is associated with negative stiffness due to the gating of the mechonoelectric transducer channel.

Effect of the cochlear microphonic on the limiting frequency of the mammalian ear.

Electromotility is a basis for cochlear amplifier, which controls the sensitivity of the mammalian ear and contributes to its frequency selectivity. Because it is driven by the receptor potential, its frequency characteristics are determined by the low-pass RC filter intrinsic to the cell, which has a corner frequency about 1/10th of the operating frequency. This filter significantly decreases the efficiency of electromotility as an amplifier. The present paper examines a proposal that the cochlear microphonic, the voltage drop across the extracellular medium by the receptor current, contributes to overcome this problem. It is found that this effect can improve frequency dependence. However, this effect alone is too small to enhance the effectiveness of electromotility beyond 10 kHz in the mammalian ear.