Dexamethasone induces stiffening of alveolar epithelial cells

Dexamethasone induces stiffening of alveolar epithelial cells

Track 13. Respiratory Mechanics Track 13 Respiratory Mechanics 4230 We-Th, no. 1 (P64) Particle distribution in four-generation obstructed lung airw...

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Track 13. Respiratory Mechanics

Track 13

Respiratory Mechanics 4230 We-Th, no. 1 (P64) Particle distribution in four-generation obstructed lung airways H.Y. Luo, '~ Liu. Department ef Mechanical Engineering, The Heng Keng

Polytechnic University, Hung Hem, Kowloon, Hong Kong Chronic Obstructive Pulmonary Disease (COPD), also called chronic obstructive lung disease, is a kind of common disease in lung. It usually results in an inflammation of the bronchi which would narrow and obstruct the airways. This obstruction alters the flow pattern and particle deposition significantly. In order to investigate the effect of COPD on the particle deposition, the multiphase flow in four different three-dimensional four-generation lung models based on the 23-generation model of Weibel (1963) are carried out using a CFD solver. A symmetric model is built as reference. The other three models are considered to be obstructed at different generation. The fully three-dimensional incompressible laminar Navier-Stokes equations and the particle transport equation are solved using hexahedral meshes. Four Reynolds Numbers, which are based on the mean velocity at the inlet and the diameter of the first-generation tube, ranging from 300 to 1200 with increment of 300, are considered in each model. For each Reynolds Number, five cases with different Stokes Numbers, 0.04, 0.06, 0.08, 0.10 and 0.12, are calculated in order to study the effect of the inertia of the particles on the particle distribution patterns. The calculated results show that particle deposition pattern is influenced significantly by the obstructed airways. Generally, the unobstructed side branches have more particles deposited on the wall. On the obstructed side, particles deposit on the inflamed surface due to inertial impaction. Due to the jet effect of obstruction, more particles would deposit on the conjunction of the bifurcation. 4145 We-Th, no. 2 (P64) Differential regulation o f pulmonary endothelial barrier recovery by varying degrees o f cyclic stretch A.A. Birukova, S. Chatchavalvanich, K.G. Birukov. Department ef Medicine,

the University of Chicago, Chicago, IL, USA Ventilator-induced lung injury is a life-threatening complication of mechanical ventilation at high tidal volumes. Besides activation of pro-inflammatory cytokine production, excessive lung distension directly affects blood-gas barrier and lung vascular permeability. To investigate whether restoration of pulmonary endothelial barrier recovery after agonist challenge is dependent on the magnitude of applied cyclic stretch and how these effects are linked to differential activation of small GTPases Rac and Rho, human pulmonary endothelial cells were subjected to physiologically (5% elongation) or pathologically (18% elongation) relevant levels of cyclic stretch. Pathological cyclic stretch enhanced thrombin-induced (50nM, 5min) stress fiber formation, gap formation, and delayed monolayer recovery (50min after thrombin stimulation). In contrast, physiological cyclic stretch induced nearly complete endothelial barrier recovery accompanied by peripheral redistribution of focal adhesions and cortactin after 50min of thrombin challenge. Consistent with differential effects on monolayer integrity, 18% cyclic stretch enhanced thrombin-induced Rho activation, whereas 5% cyclic stretch promoted Rac activation during endothelial barrier recovery phase. Downregulation of Rac activity by pharmacological inhibitor NSC-23766 (200pM, 1 hr) or Rac protein depletion using siRNAbased approach dramatically attenuated restoration of monolayer integrity after thrombin challenge. In addition, physiological cyclic stretch preconditioning (5% stretch, 24 hrs) enhanced endothelial cell paracellular gap resolution after step-wise increase to 18% stretch (30 min) and thrombin challenge. Our novel data suggest for the first time a critical role for the cyclic stretch amplitude and the balance between small GTPases Rac and Rho in mechanochemical regulation of lung endothelial barrier. 4239 We-Th, no. 3 (P64) Use o f computational fluid dynamics for respiratory units to simulate air-flow through a radial fan N. Sampat, M. Gabi. Department ef Fluid Machinery, Faculty Mechnaical

Engineering, University Karlsruhe, Germany In medical care units for emergency and transport ventilation, respiratory units have been proven to be very useful for patients unable to breath on their own or who have a limited ability for it. Such units can support or even substitute totally the spontaneous gas-exchange between the environment and the lungs. In cases like paralysis of the natural airway, brain-complications or bloodcirculatory disorder, respiratory units become necessary and are based on the natural breathing technique which involves the very delicate lungs.

$593 The common computer-regulated respiratory unit has an air-tank and welldefined medically grounded modes likethe Positive End Expiratory Pressure mode, to pump air in the lungs. An air-tank is heavy and cumbersome and as a first step to replace it, a computer-model of a small radial fan with simple blades and a spiral casing is proposed, which fulfills the medical requirements of a given flow rate and overpressure. In literature, some simplified models do exist in order to predict the air-flow through simple radial blades, yet an exact theoretical concept for the shape and number of blades is not available but some rules can be obtained through the CORDIER-DIAGRAM which is based on experimental work. Based on these limitations, for computer simulations, a trial-and-error method was hence put to practice. The computer model of a radial fan with spiral casing was constructed through commercial software-program ICEM used as the mesh-generator. The flow was treated as incompressible, turbulent and the transient case was solved through the Moving-Reference-Frame technique with computational fluid dynamics software STAR-CD which is based on finite-volume method. Results of the flow-simulations will be presented and compared with the medical requirements of overpressure 4000 Pa and a maximum flow rate of 150 liter per minute. 4401 We-Th, no. 4 (P64) 3D-Spirogram: a combinatory system o f image analysis and computational mechanics H. Kitaoka, T. Kijima, I. Kawase. Dept. of Respiratory Disease, Graduate

School of Medicine, Osaka University, Japan Purpose: We have been developing an integrated system for analyzing and simulating the pulmonary function by the use of multi-phase 3D-CT data set of the lung. "3D-Spirogram" is to estimate intra-pulmonary distributions of ventilation, ventilation-perfusion ratio, airflow conductance, and tissue compliance. Methods: 3D-CT data at FRC, FRC+TV, and TLC were acquired at supine postures. Intra-pulmonary displacement vector field of the lung structure was obtained by a non-rigid image registration technique. Ventilation ratio (VR), defined as the increased volume in lung tissue for a unit volume at expiration, was obtained for each voxel. We defined ventilation-tissue mass ratio (VTR, ml/g) as the inhaled air volume per unit mass of lung tissue which is estimated from the CT value. The VTR is approximately equivalent to ventilation-perfusion ratio (VQR) if there are no exudative changes. Inhaled air flow was simulated by CFD method under the assumption of steady laminar flow with free outlet boundary conditions. Relative flow conductances to respective lobes were then obtained by dividing flow rates to lobar bronchi by lobar volumes at expiratory phase. Distribution of tissue compliance was sought as a reverse problem of linear static structural analysis of the lung FE model so as to reproduce the displacement vector field obtained by real CT data analysis. Results: The spatial distribution of VR was consistent with other clinical tests. Histograms of VTR in normal and emphysema cases were similar to those of VQR in literatures. Calculated spatial distributions of the air flow conductance and the compliance were conceivable, although there are no methods to examine the accuracies. Conclusion: Distributions of ventilation ratio and ventilation-tissue mass ratio are useful and practical as clinical tests. Although estimations of airflow conductance and tissue compliance require more improvements, the 3D spirogram will be a useful method for investigating respiratory pathophysiology. 6480 We-Th, no. 5 (P64) Dexamethasone induces stiffening o f alveolar epithelial cells E Puig, N. Gavara, R. Sunyer, D. Navajas, R. Farr6. Unitat Biofisica i

Bioenginyeria, Facultat Medicina, Universitat Barcelona-IDIBAPS, Barcelona,

spain Acute lung injury is characterized by disruption of the alveolar-capillary barrier. The structural integrity of the alveolar monolayer is regulated by the balance between cell-cell and cell-matrix tethering forces and centripetal forces arising from cytoskeletal tension. Drugs altering cell mechanical properties could modify this force balance and mediate barrier integrity. Dexamethasone, an antiinflammatory drug with protective effects in acute lung injury, has been shown to induce remodelling of cell cytoskeleton. The aim of this work was to study the effects of dexamethasone on the viscoelastic properties of cultured human alveolar epithelial cells. Cell viscoelasticity was assessed by optical magnetic twisting cytometry. Alveolar epithelial cells A549 were plated on 6.4 mm plastic wells. After 24 hours of incubation with dexamethasone 1 ~tM (n = 11 ) or vehicle (0.01% DMSO) (n = 11), ferromagnetic microbeads coated with RGD peptide were attached to the cell surface. The beads were magnetized (150 mT) and sinusoidally twisted (3mT, 0.1 Hz). Cell storage (G/) and loss (G') moduli and the loss tangent ('q = G ' / G ~) were computed from twisting torque and bead displacement. In control cells, G/, G ~ and 'q were 1264.7±81.5Pa, 390.3±32.3Pa and 0.318±0.008, respectively (mean±SE). In dexamethasone treated cells, both G ~ and GPrime; were significantly higher than in controls: G~= 1978±226Pa (p<0.01) and G ' = 5 7 2 . 5 ± 5 3 . 5 P a (p<0.01). The


Journal o f Biomechanics 2006, Vol. 39 (Suppl 1)

loss tangent in dexamethasone treated cells was 'q =0.312±0.005) (p =0.52 vs. control). Therefore, dexamethasone stiffens A549 alveolar epithelial cells by inducing a parallel increase in both the elastic and loss moduli. Cell stiffening results in increased elastic centripetal forces during the cell stretching associated with breathing or mechanical ventilation. Cell-cell and cell-matrix adhesion forces should counterbalance the increased elastic forces to maintain monolayer integrity. Supported in part by: SAF 2005q30110 and FIS-PI040929. 6244 We-Th, no. 6 (P64) Computer-aided segmentation and quantification of the human airway tree on the basis o f multi CT images T. Miki 1, S. Wada 1, M. Nakamura 1, K.-i. Tsubota 1, T. Yamaguchi 1, '~ Suda 2, G. Tamura 3 . 1Department of Bioengineering and Robotics, Tohoku University,

Sendal, Japan, 2Sendal Open Hospital, Sendal, Japan, 3 Tohoku University Hospital, Sendal, Japan Morphological structure of the airways is related to a respiratory function. To improve the diagnosis of pulmonary diseases such as asthma, we developed an algorithm for automated segmentation and quantification of the human airway tree on the basis of multi CT images of the lung. The algorithm consists of segmentation of the airway tree, its skeletonization, identification of the airway generation, and measurement of volume, length and diameter of each airway. CT images were acquired with the up-to-date multi slice CT scanner, Aquillion64 (Toshiba Medical Systems Corp., Japan). The airway lumen was extracted from CT images with the region growing method; a grayscale intensity specific to a tissue of the airway wall was determined in the CT images at the entrance of trachea and it was handed to subsequent CT images to trace and construct a 3-D airway model of the airway tree. For morphometric identification of airways' branching, the 3-D airway model was skeletonized. Although the current skeletonization algorithm yielded some pseudo branches, those were deleted manually. Given the skeletonized model, the generation number was defined to each branch of the airway model. A diameter of a branch was calculated under the assumption that the branch was truly cylindrical. The results showed it was possible to extract up to the 14th generation of the airway tree whose diameter was 1.7 mm. The airway diameters obtained were in good agreement with those reported in autopsy study (Weibel et al., 1963), although the diameters on and after 8th generation were all larger than those in Weibel et al. (1963) due probably to an insufficient resolution of CT images. These results addressed the validity of the algorithm developed in this study in quantification of the airway tree. References Weibel et al. (1963). Morphometry of the Human Lung. Academic Press Inc., New York, p. 139.

6162 We-Th, no. 7 (P64) Relationship between ozone absorption and uric acid concentration in the human nasal cavities J.S. Ultman 1, A. Fassih 1, L.Y. Santiago 2, A. Ben-Jebria 1. 1Department ef

Chemical Engineering, Penn State University, University Park, Pennsylvania, USA, 2Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA The nose protects the lower respiratory tract by extracting oxidative air pollutants such as ozone (03) from inhaled air by chemical reaction with nasal antioxidants such as uric acid (UA). The purpose of this study was to quantify the relationship between the fractional uptake of 03 in the nasal cavities (Ao3) and the corresponding concentration of UA in nasal lavage samples (CuA). Measurements of Ao3 were performed in triplicate using an apparatus that supplied a 3 - 5 Lpm stream of air containing 0.36 ppm 03 to one nostril and monitored 03 concentration in air exiting the second nostril while a subject kept their glottis in a closed position. Nasal lavage samples were processed by HPLC to determine CUA. Three different experiments were performed on healthy adult nonsmokers: in a day-to-day variability study, 15 subjects reported to the laboratory on three separate days during which Ao3 measurement was made immediately before a single nasal lavage sample was taken; in a sequential washing study, a series of three sets of Ao3 measurements, each immediately followed by nasal lavage, were made on 11 subjects during a single visit to the lab; and in an 03 exposure study, performed on 11 subjects during a single lab visit, an initial Ao3 measurement and nasal lavage was following by a 30-minute continuous exposure to 0.36 ppm 03 before a final Ao3 measurement and nasal lavage were performed. The natural day-to-day variations of Ao3 in the first study were not correlated with CUA (P >0.4). On the other hand, the systematic changes in Ao3 that were induced either by sequential washings or by continuous 03 exposure were both significantly correlated with CUA (P <0.05). The combination of a onedimensional convection-diffusion model of gas transport in the nasal airways with a reaction-diffusion model of gas uptake into the surrounding mucous

Poster Presentations

layer allowed us to estimate a second-order rate constant of 6x10 s L/mol-s for the chemical reaction between 03 and UA. Supported in part by a research grant from the Philip Morris External Research Program. 6328 We-Th, no. 8 (P64) Theoretical study of gas exchange in total liquid ventilation H. Fujioka 1, S. Tredici 2, R.B. Hirschl 2, R.H. Bartlett 2, J.B. Grotberg 1,2.

1Biomedical Engineering Department, University of Michigan, Ann Arbor, USA, 2Department of General Surgery, University of Michigan, Ann Arbor, USA Diseases such as adult respiratory distress syndrome and neonatal respiratory distress syndrome (hyaline membrane disease) are characterized by less compliant lungs, a result of insufficient surfactant production or effectiveness. Total liquid ventilation (TLV) is an artificial ventilation system which uses perfluorocarbon (PFC) liquid to eliminate the air-liquid interface. PFC has high solubilities of oxygen and carbon-dioxide. In TLV, the convective transport in PFC is an important factor for gas exchange in the alveolar region because the diffusivities of oxygen and carbon dioxide in PFC are four orders of magnitude lower than in air. In this study, a computational model for gas exchange in the lung is developed: a conducting airways branching network is modeled as a trumpet-shaped tube; the terminal alveolar sac is modeled as an oscillating spherical shell; a tissue and capillary blood are modeled as wellmixed compartments; and mixed-venous gas partial pressures are calculated assuming a constant oxygen consumption and carbon dioxide production. Since the convection dominates the transport in the sac as well as in the conducting airways, steep partial pressure gradients in the sac exist from the middle of inspiration to the beginning of expiration. End-inspiratory dwell-time enhances gas exchange rate. Our computational results for the arterial gas partial pressures were agreed well with the experimental results of TLV for rabbits. This work is supported by NIH grant HL64373. 6370 We-Th, no. 9 (P64) Flow o f aerosol in a 3D alveolated bend: experimental measurements by Particle Image Velocimetry (PIV) and Particle Tracking Velocimetry (PTV) P. Corieri 1, R. Theunissen 1, N. Buchmann 1, C. van Ertbruggen 2, C. Darquenne 2, M.L. Riethmuller 1. l v o n Karman Institute for Fluid Dynamics,

Rhode-St-Genese, Belgium, 2Dept. Medicine, University of California San Diego, La Jolla, USA Understanding the transport of inhaled particles in the alveolar region of the lung is important whether particle exposure results from pollution or inhaled drug therapy. Aerosol transport mechanisms are however not yet fully understood despite their investigation in numerous computational studies. Furthermore, because of the absence of in-vivo measurements, these computational studies lack experimental validation. We built a 3D scaled-up model of a curved pipe with circular cavities representative of the alveolar region of the lung in which both flow velocities and aerosol trajectories were measured by PIV and PTV, respectively. Measurements provided a comprehensive dataset for validation of numerical simulations performed in a similar model. Silicone oil was used as carrier fluid and 1.2 mmdiameter iron particles were used. Flow rate was 0.84 ml/s (Re = 0.07). These experimental conditions were representative of transport of 12.8 ~tm-diameter aerosol in the acinus. Flow field was characterised by a curvilinear separation streamline at the alveolar openings, indicating little convective exchange between the alveoli and the lumen. In the lumen, velocity profiles agreed with Poiseuille flow. In each alveolar cavity, slow rotating fluid elements could be identified with the advanced interrogation methodology. Velocities inside these cavities were about two orders of magnitude smaller than the mean lumen velocity. These data validate numerical simulations presented in a separate paper. PTV data showed that particles did not follow the streamlines. Because Stokes number along the particle trajectories was - 1 0 -4 , inertial forces were negligible and particles behaviour was mainly affected by viscous forces suggesting that deviation from the streamlines resulted from gravity. In conclusion, we showed that both PIV and PTV can be successfully used to track particle trajectories under Stokes flow conditions present in the alveolar region of the lung. These techniques can therefore reliably be used in future investigations of aerosol behaviour in more complex acinar models.