Effect of gravity on liquid plug transport through an airway bifurcation model

Many medical therapies require liquid plugs to be instilled into and delivered throughout the pulmonary airways. Improving these treatments requires a better understanding of how liquid distributes throughout these airways. In this study, gravitational and surface mechanisms determining the distribution of instilled liquids are examined experimentally using a bench-top model of a symmetrically bifurcating airway. A liquid plug was instilled into the parent tube and driven through the bifurcation by a syringe pump. The effect of gravity was adjusted by changing the roll angle (phi) and pitch angle (gamma) of the bifurcation (phi = gamma =0 deg was isogravitational). Phi determines the relative gravitational orientation of the two daughter tubes: when phi not equal to 0 deg, one daughter tube was lower (gravitationally favored) compared to the other. Gamma determines the component of gravity acting along the axial direction of the parent tube: when gamma not equal to 0 deg, a nonzero component of gravity acts along the axial direction of the parent tube. A splitting ratio Rs, is defined as the ratio of the liquid volume in the upper daughter to the lower just after plug splitting. We measured the splitting ratio, Rs, as a function of: the parent-tube capillary number (Cap); the Bond number (Bo); phi; gamma; and the presence of pre-existing plugs initially blocking either daughter tube. A critical capillary number (Cac) was found to exist below which no liquid entered the upper daughter (Rs = 0), and above which Rs increased and leveled off with Cap. Cac increased while Rs decreased with increasing phi, gamma, and Bo for blocked and unblocked cases at a given Cap > Ca,. Compared to the nonblockage cases, Rs decreased (increased) at a given Cap while Cac increased (decreased) with an upper (lower) liquid blockage. More liquid entered the unblocked daughter with a blockage in one daughter tube, and this effect was larger with larger gravity effect. A simple theoretical model that predicts Rs and Cac is in qualitative agreement with the experiments over a wide range of parameters.     

Liquid plug flow in straight and bifurcating tubes.

A finite-length liquid plug may be present in an airway due to disease, airway closure, or by direct instillation for medical therapy. Air forced by ventilation propagates the plug through the airways, where it deposits fluid onto the airway walls. The plug may encounter single or bifurcating airways, an airway surface liquid, and other liquid plugs in nearby airways. In order to understand how these flow situations influence plug transport, benchtop experiments are performed for liquid plug flow in: Case (i) straight dry tubes, Case (ii) straight pre-wetted tubes, Case (iii) bifurcating dry tubes, and Case (iv) bifurcating tubes with a liquid blockage in one daughter. Data are obtainedfor the trailing film thickness and plug splitting ratio as a function of capillary number and plug volumes. For Case (i), the finite length plug in a dry tube has similar behavior to a semi-infinite plug. For Case (ii), the trailing film thickness is dependent upon the plug capillary number (Ca) and not the precursor film thickness, although the shortening or lengthening of the liquid plug is influenced by the precursor film. For Case (iii), the plug splits evenly between the two daughters and the deposited film thickness depends on the local plug Ca, except for a small discrepancy that may be due to an entrance effect or from curvature of the tubes. For Case (iv), a plug passing from the parent to daughters will deliver more liquid to the unblocked daughter (nearly double, consistently) and then the plug will then travel at greater Ca in the unblocked daughter as the blocked. The flow asymmetry is enhanced for a larger blockage volume and diminished for a larger parent plug volume and parent-Ca.     

下呼吸道重开的生物流体力学研究:实验模拟

实验模拟了受阻塞肺下呼吸道重开的生物力学问题。呼吸是玻璃直圆管,以具有生物流体性质的机油作为阻塞液。实验给同了在压强差作用下阻塞液柱前陈面以及主粘液柱气泡前阵面的位置和速度曲线。结果表明,它们受外加压强,管直径,阻塞液以及初始阻塞液长度的影响。较高的外加中、阻塞液粘度较你攻管径较粗有利于呼吸道的重开。     

Sympathetic and parasympathetic nervous control of airway resistance in dog lungs

We studied autonomic nervous control of central (Rc), peripheral (Rp), and extremely peripheral (Rep) airway resistances using a combination of a retrograde catheter method and a pleural capsule method. Airflow through the pleural capsule enabled us to measure Rep, which mainly reflected the resistance of local bronchioles less than 0.6 mm in diameter. Rp of the airways less than about 2 mm in diameter was not negligibly small at any lung volume (VL). With vagi intact, Rc increased at high as well as low VL, whereas Rp and Rep increased sharply as VL decreased. Vagal stimulation increased Rp more markedly than Rc, and Rep least of all. Propranolol augmented total airway resistance (Rtot) two to four times as much as vagal stimulation, mainly because of increased Rp. Stimulation of stellate ganglia inhibited up to half the increase of Rtot elicited by vagal stimulation; most of the inhibition occurred in Rp, but little in Rc and Rep. Our data suggest that both sympathetic and parasympathetic control is more extensive for Rp than for Rc or Rep.     

Computational analysis of flow structure and particle deposition in a single asthmatic human airway bifurcation

This paper aims to improve current understanding of flow structure and particle deposition in asthmatic human airways. A single, symmetric airway bifurcation, corresponding to generations 10–11 of Weibel’s model, is investigated through validated numerical simulations. The parent airway segment is modelled as a smooth circular tube. The child segments are considered asthmatic and their cross-section is modelled as a constricted tube with sinusoidal folds uniformly distributed along the circumference. The flow structure and particle deposition pattern for normal (i.e., healthy) and asthmatic airway bifurcations are compared and discussed. The numerical results reveal that the secondary flow in the asthmatic airway bifurcation is much stronger than in the healthy one, resulting in higher particle deposition. The effects of size of the lumen area and number of folds on particle deposition and pressure drop are also investigated. It is found that particle deposition efficiency is significantly affected by lumen area of the asthmatic segment (the smaller the lumen area, the higher the particle deposition efficiency). The effect of number of folds is small. Particle deposition efficiency also increases with Reynolds number. The pressure drop in the asthmatic airway bifurcation depends mainly on size of the lumen area. The effect of number of folds becomes important for strongly collapsed airways.     

An analysis of pollutant gas transport and absorption in pulmonary airways

A mathematical model of ozone absorption, or for any soluble gas that has similar transport properties, is developed for a branching network of liquid-lined cylinders. In particular, we investigate specific flow regimes for finite length tubes where boundary layer phenomena and entrance effects exist in high Reynolds and Peclet (Pe) number airways. The smaller airways which have lower Reynolds and Peclet number flows are modelled by incorporating the detailed analysis found in [10] and modifying it for airways which have alveolated surfaces. We also consider a reacting gas and treat specific regimes where the reaction front is located at the air-liquid interface, within the liquid or at the liquid-tissue interface. Asymptotic methods are used in regions of the tracheobronchial tree where Pe much less than 1 and Pe much greater than 1. In addition, the fact that the radial transport parameter gamma much less than 1 for this toxin, and others such as nitrous oxides, is employed to simplify the analysis. The ozone concentrations, airway absorption and tissue dose are examined as a function of airway generation for several values of the governing parameters. The general result is a maximal dosing in airway generations 17 to 18 that is much larger (up to an order of magnitude) than the predictions of previous theories.     

Dominant-negative effect of truncated mannose 6-phosphate/insulin-like growth factor II receptor species in cancer

Oligomerization of the mannose 6-phosphate/insulin-like growth factor?II receptor (M6P/IGF2R) is important for optimal ligand binding and internalization. M6P/IGF2R is a tumor suppressor gene that exhibits loss of heterozygosity and is mutated in several cancers. We tested the potential dominant-negative effects of two cancer-associated mutations that truncate M6P/IGF2R in ectodomain repeats 9 and 14. Our hypothesis was that co-expression of the truncated receptors with the wild-type/endogenous full-length M6P/IGF2R would interfere with M6P/IGF2R function by heterodimer interference. Immunoprecipitation confirmed formation of heterodimeric complexes between full-length M6P/IGF2Rs and the truncated receptors, termed Rep9F and Rep14F. Remarkably, increasing expression of either Rep9F or Rep14F provoked decreased levels of full-length M6P/IGF2Rs in both cell lysates and plasma membranes, indicating a dominant-negative effect on receptor availability. Loss of full-length M6P/IGF2R was not due to increased proteasomal or lysosomal degradation, but instead arose from increased proteolytic cleavage of cell-surface M6P/IGF2Rs, resulting in ectodomain release, by a mechanism that was inhibited by metal ion chelators. These data suggest that M6P/IGF2R truncation mutants may contribute to the cancer phenotype by decreasing the availability of full-length M6P/IGF2Rs to perform tumor-suppressive functions such as binding/internalization of receptor ligands such as insulin-like growth factor II.     

Role of aquaporin water channels in airway fluid transport, humidification, and surface liquid hydration

Several aquaporin-type water channels are expressed in mammalian airways and lung: AQP1 in microvascular endothelia, AQP3 in upper airway epithelia, AQP4 in upper and lower airway epithelia, and AQP5 in alveolar epithelia. Novel quantitative methods were developed to compare airway fluid transport-related functions in wild-type mice and knockout mice deficient in these aquaporins. Lower airway humidification, measured from the moisture content of expired air during mechanical ventilation with dry air through a tracheotomy, was 54-56% efficient in wild-type mice, and reduced by only 3-4% in AQP1/AQP5 or AQP3/AQP4 double knockout mice. Upper airway humidification, measured from the moisture gained by dry air passed through the upper airways in mice breathing through a tracheotomy, decreased from 91 to 50% with increasing ventilation from 20 to 220 ml/min, and reduced by 3-5% in AQP3/AQP4 knockout mice. The depth and salt concentration of the airway surface liquid in trachea was measured in vivo using fluorescent probes and confocal and ratio imaging microscopy. Airway surface liquid depth was 45 +/- 5 microm and [Na(+)] was 115 +/- 4 mM in wild-type mice, and not significantly different in AQP3/AQP4 knockout mice. Osmotic water permeability in upper airways, measured by an in vivo instillation/sample method, was reduced by approximately 40% by AQP3/AQP4 deletion. In doing these measurements, we discovered a novel amiloride-sensitive isosmolar fluid absorption process in upper airways (13% in 5 min) that was not affected by aquaporin deletion. These results establish the fluid transporting properties of mouse airways, and indicate that aquaporins play at most a minor role in airway humidification, ASL hydration, and isosmolar fluid absorption.     

Cloning of the Bacillus subtilis recE+ gene and functional expression of recE+ in B. subtilis.

By use of the Bacillus subtilis bacteriophage cloning vehicle phi 105J23, B. subtilis chromosomal MboI fragments have been cloned that alleviate the pleiotropic effects of the recE4 mutation. The recombinant bacteriophages phi 105Rec phi 1 (3.85-kilobase insert) and phi 105Rec phi 4 (3.3-kilobase insert) both conferred on the recE4 strain YB1015 resistance to ethylmethane sulfonate, methylmethane sulfonate, mitomycin C, and UV irradiation comparable with the resistance observed in recE+ strains. While strain YB1015 (recE4) and its derivatives lysogenized with bacteriophage phi 105J23 were not transformed to prototrophy by B. subtilis chromosomal DNA, strain YB1015 lysogenized with either phi 105Rec phi 1 or phi 105Rec phi 4 was susceptible to transformation with homologous B. subtilis chromosomal DNA. The heteroimmune prophages phi 105 and SPO2 were essentially uninducible in strain YB1015. Significantly, both recombinant prophages phi 105Rec phi 1 and phi 105Rec phi 4 were fully inducible and allowed the spontaneous and mitomycin C-dependent induction of a coresident SPO2 prophage in a recE4 host. The presence of the recombinant prophages also restored the ability of din genes to be induced in strains carrying the recE4 mutation. Finally, both recombinant bacteriophages elaborated a mitomycin C-inducible, 45-kilodalton protein that was immunoreactive with Escherichia coli recA+ gene product antibodies. Collectively, these data demonstrate that the recE+ gene has been cloned and that this gene elaborates the 45-kilodalton protein that is involved in SOB induction and homologous recombination.     

A theoretical study of surfactant and liquid delivery into the lung

A computational study is presented for thetransport of liquids and insoluble surfactant through the lung airways,delivered from a source at the distal end of the trachea. Four distinct transport regimes are considered: 1)the instilled bolus may create a liquid plug that occludes the largeairways but is forced peripherally during mechanical ventilation;2) the bolus creates a deposited film on the airway walls, either from the liquid plug transport or fromdirect coating, that drains under the influence of gravity through thefirst few airway generations; 3) insmaller airways, surfactant species form a surface layer that spreadsdue to surface-tension gradients, i.e., Marangoni flows; and4) the surfactant finally reachesthe alveolar compartment where it is cleared according to first-orderkinetics. The time required for a quasi-steady-state transport processto evolve and for the subsequent delivery of the dose is predicted.Following fairly rapid transients, on the order of seconds,steady-state transport develops and is governed by the interaction ofMarangoni flow and alveolar kinetics. Total delivery time is ~24 hfor a typical first dose. Numerical solutions show that both transitand delivery times are strongly influenced by the strength of thepreexisting surfactant and the geometric properties of the airwaynetwork. Delivery times for follow-up doses can increase significantlyas the level of preexisting surfactant rises.

     

A rat lung model of instilled liquid transport in the pulmonary airways.

When a liquid is instilled in the pulmonary airways during medical therapy, the method of instillation affects the liquid distribution throughout the lung. To investigate the fluid transport dynamics, exogenous surfactant (Survanta) mixed with a radiopaque tracer is instilled into tracheae of vertical, excised rat lungs (ventilation 40 breaths/min, 4 ml tidal volume). Two methods are compared: For case A, the liquid drains by gravity into the upper airways followed by inspiration; for case B, the liquid initially forms a plug in the trachea, followed by inspiration. Experiments are continuously recorded using a microfocal X-ray source and an image-intensifier, charge-coupled device image train. Video images recorded at 30 images/s are digitized and analyzed. Transport dynamics during the first few breaths are quantified statistically and follow trends for liquid plug propagation theory. A plug of liquid driven by forced air can reach alveolar regions within the first few breaths. Homogeneity of distribution measured at end inspiration for several breaths demonstrates that case B is twice as homogeneous as case A. The formation of a liquid plug in the trachea, before inspiration, is important in creating a more uniform liquid distribution throughout the lungs.     

Evolutionary comparison of murine and human delta T-cell receptor deleting elements

The gene for the T-cell antigen receptor (TCR) delta chain is a gene within a gene, being located in the TCR alpha chain gene in both mice and humans. The human delta locus is flanked by delta deleting elements that undergo preferential rearrangement in the thymus, resulting in deletion of internal delta coding segments. The mouse has conserved analogous elements, m delta Rec and m phi J alpha, which separate delta from alpha and undergo a m delta Rec/m phi J alpha rearrangement in polyclonal thymus. The 5' element, m delta Rec, which is an isolated heptamer-spacer-nonamer (h-s-n), lies within 200 kb of D delta 1, and displays two areas of nearly 80% homology to human delta Rec. The downstream element, m phi J alpha, lies 12.5 kb 3' to C delta, lacks the consensus amino acids for J alpha, and retains 80% homology to human phi J alpha. Cells from murine neonatal thymus show three prominent m delta Rec rearrangements consisting of the m delta Rec/m phi J alpha recombination, a delta Rec/D delta 1/D delta 2/J delta 1 recombination, and two hybrid recombinations. A consequence of the m delta Rec/M phi J alpha rearrangement is a deletion of internal D delta and J delta coding segments that would prevent their incorporation into alpha TCR products. The conservation of noncoding deleting elements flanking the delta TCR in mice and humans is similar to the evolutionarily preserved kappa deleting element of the B-cell lineage and argues for an important role in receptor utilization.     

Criteria for mucus transport in the airways by two-phase gas-liquid flow mechanism

The critical conditions for mucous layer transport in the respiratory airways by two-phase gas-liquid flow mechanism were investigated by using 0.5- and 1.0-cm-ID tube models. Several test liquids with rheological properties comparable to human sputum were supplied continuously into the vertically positioned tube models in such a way that the liquid could form a uniform layer while traveling upward through the tube with a continuous upward airflow. The critical airflow rate and critical liquid layer thickness required for the upward transport of the liquids were determined. The critical airflow rate was in the Reynolds number (Re) range of 142-1,132 in the 0.5-cm-ID tube model and 708-2,830 in the 1.0-cm-ID tube model depending on the types of liquids tested. In both models, the critical airflow rate was lower with viscoelastic liquids than with viscous oils. The critical liquid layer thickness ranged from 0.2 to 0.5 mm in the 0.5-cm-ID tube model and 0.8 to 1.4 mm in the 1.0-cm-ID tube model at Re of 2,800. These values decreased rapidly with increasing airflow rate. The critical thickness relative to the tube diameter ranged from 3 to 15% of the respective tube diameter and was lower by approximately 30-50% in the 0.5-cm-ID tube model than in the 1.0-cm-ID tube model over the entire Re range tested. The results indicate that the critical conditions for the mucus transport by two-phase gas-liquid flow mechanism are within the range that can be achieved in patients with bronchial hypersecretions during normal breathing.     

Oscillatory flow and gas transport through a symmetrical bifurcation

Axial gas transport due to the interaction between radial mixing and radially nonuniform axial velocities is responsible for gas transport in thick airways during High-frequency oscillatory ventilation (HFO). Because the airways can be characterized by a bifurcating tube network, the secondary flow in the curved portion of a bifurcating tube contributes to cross-stream mixing. In this study the oscillatory flow and concentration fields through a single symmetrical airway bifurcating tube model were numerically analyzed by solving three-dimensional Navier-Stokes and mass concentration equations with the SIMPLER algorithm. The simulation conditions were for a Womersley number, alpha = 9.1 and Reynolds numbers in the parent tube between 200 and 1000, corresponding to Dn2/alpha 4 in the curved portion between 2 and 80, where Dn is Dean number. For comparison with the results from the bifurcating tube, we calculated the velocity and concentration fields for fully developed oscillatory flow through a curved tube with a curvature rate of 1/10, which is identical to the curved portion of the bifurcating tube. For Dn2/alpha 4 < or = 10 in the curved portion of the bifurcating tube, the flow divider and area changes dominate the axial gas transport, because the effective diffusivity is greater than in either a straight or curved tube, in spite of low secondary velocities. However, for Dn2/alpha 4 > or = 20, the gas transport characteristics in a bifurcation are similar to a curved tube because of the significant effect of secondary flow.     

Small-bubble transport and splitting dynamics in a symmetric bifurcation

Simulations of small bubbles traveling through symmetric bifurcations are conducted to garner information pertinent to gas embolotherapy, a potential cancer treatment. Gas embolotherapy procedures use intra-arterial bubbles to occlude tumor blood supply. As bubbles pass through bifurcations in the blood stream nonhomogeneous splitting and undesirable bioeffects may occur. To aid development of gas embolotherapy techniques, a volume of fluid method is used to model the splitting process of gas bubbles passing through artery and arteriole bifurcations. The model reproduces the variety of splitting behaviors observed experimentally, including the bubble reversal phenomenon. Splitting homogeneity and maximum shear stress along the vessel walls is predicted over a variety of physical parameters. Small bubbles, having initial length less than twice the vessel diameter, were found unlikely to split in the presence of gravitational asymmetry. Maximum shear stresses were found to decrease exponentially with increasing Reynolds number. Vortex-induced shearing near the bifurcation is identified as a possible mechanism for endothelial cell damage.     

Capillary-elastic instabilities of liquid-lined lung airways

To model the competition between capillary and elastic forces in controlling the shape of a small lung airway and its interior liquid lining, we compute the equilibrium configurations of a liquid-lined, externally pressurized, buckled elastic tube. We impose axial uniformity and assume that the liquid wets the tube wall with zero contact angle. Non-zero surface tension has a profound effect on the tube's quasi-steady inflation-deflation characteristics. At low liquid volumes, hysteresis arises through two distinct mechanisms, depending on the buckling wavenumber. Sufficient compression always leads to abrupt and irreversible collapse and flooding of the tube; flooding is promoted by increasing liquid volumes or surface tension. The model captures mechanisms whereby capillary-elastic instabilities can lead to airway closure.     

A three-dimensional model of the upper tracheobronchial tree

A new model of the upper tracheobronchial tree is proposed to account for the three-dimensional nature of the airway system. In addition to the tube length, the tube diameter, and the branching angle, the model includes information on the orientation angle of each tube relative to its parent tube. The orientation angle, defined as the angle between two successive bifurcations, is useful for calculating the gravitational inclination of each tube. The information on orientation angle is further used to construct a binary coding system for identifying individual tubes in the airway tree. The proposed model is asymmetrical, but the same principles can be readily used to construct a symmetrical one.     

Rat airway morphometry measured from in situ MRI-based geometric models

Rodents have been widely used to study the environmental or therapeutic impact of inhaled particles. Knowledge of airway morphometry is essential in assessing geometric influence on aerosol deposition and in developing accurate lung models of aerosol transport. Previous morphometric studies of the rat lung performed ex situ provided high-resolution measurements (50-125 μm). However, it is unclear how the overall geometry of these casts might have differed from the natural in situ appearance. In this study, four male Wistar rat (268 ± 14 g) lungs were filled sequentially with perfluorocarbon and phosphate-buffered saline before being imaged in situ in a 7-T magnetic resonance (MR) scanner at a resolution of 0.2 × 0.2 × 0.27 mm. Airway length, diameter, gravitational, bifurcation, and rotational angles were measured for the first four airway generations from 3D geometric models built from the MR images. Minor interanimal variability [expressed by the relative standard deviation RSD (=SD/mean)] was found for length (0.18 ± 0.07), diameter (0.15 ± 0.15), and gravitational angle (0.12 ± 0.06). One rat model was extended to 16 airway generations. Organization of the airways using a diameter-defined Strahler ordering method resulted in lower interorder variability than conventional generation-based grouping for both diameter (RSD = 0.12 vs. 0.42) and length (0.16 vs. 0.67). Gravitational and rotational angles averaged 82.9 ± 37.9° and 53.6 ± 24.1°, respectively. Finally, the major daughter branch bifurcated at a smaller angle (19.3 ± 14.6°) than the minor branch (60.5 ± 19.4°). These data represent the most comprehensive set of rodent in situ measurements to date and can be used readily in computational studies of lung function and aerosol exposure.     

A new drift-flux model for particle transport and deposition in human airways

Particle deposition and transport in human airways isfrequently modeled numerically by the Lagrangian approach. Current formulations of such models always require some ad hoc assumptions, and they are computationally expensive. A new drift-flux model is developed and incorporated into a commercial finite volume code. Because it is Eulerian in nature, the model is able to simulate particle deposition patterns, distribution and transport both spatially and temporally. Brownian diffusion, gravitational settling, and electrostatic force are three major particle deposition mechanisms in human airways. The model is validated against analytical results for three deposition mechanisms in a straight tube prior to applying the method to a single bifurcation G3-G4. Two laminar flows with Reynolds numbers 500 and 2000 are simulated. Particle concentration contour deposition pattern, and enhancement factor are evaluated. To demonstrate how the diffusion and settling influence the deposition and transport along the bifurcation, particle sizes from 1 nm to 10 microm are studied. Different deposition mechanisms can be combined into the mass conversation equation. Combined deposition efficiency for the three mechanisms simultaneously was evaluated and compared with two commonly used empirical expressions.     

Effect of ventilation rate on instilled surfactant distribution in the pulmonary airways of rats.

Liquid can be instilled into the pulmonary airways during medical procedures such as surfactant replacement therapy, partial liquid ventilation, and pulmonary drug delivery. For all cases, understanding the dynamics of liquid distribution in the lung will increase the efficacy of treatment. A recently developed imaging technique for the study of real-time liquid transport dynamics in the pulmonary airways was used to investigate the effect of respiratory rate on the distribution of an instilled liquid, surfactant, in a rat lung. Twelve excised rat lungs were suspended vertically, and a single bolus (0.05 ml) of exogenous surfactant (Survanta, Ross Laboratories, Columbus, OH) mixed with radiopaque tracer was instilled as a plug into the trachea. The lungs were ventilated with a 4-ml tidal volume for 20 breaths at one of two respiratory rates: 20 or 60 breaths/min. The motion of radiodense surfactant was imaged at 30 frames/s with a microfocal X-ray source and an image intensifier. Dynamics of surfactant distribution were quantified for each image by use of distribution statistics and a homogeneity index. We found that the liquid distribution depended on the time to liquid plug rupture, which depends on ventilation rate. At 20 breaths/min, liquid was localized in the gravity-dependent region of the lung. At 60 breaths/min, the liquid coated the airways, providing a more vertically uniform liquid distribution.