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Béla Suki

Publications and source records attributed to Béla Suki.

At least 19 recordsLinked to original sources
PubMed2006

Contributions of the active and passive components of the cytoskeletal prestress to stiffening of airway smooth muscle cells.

Airway smooth muscle cells exhibit stiffening during contractile activation. This stiffening may be interpreted as a result of the stabilizing influence of the mechanical prestress stored within the cytoskeleton (CSK). However, in vivo, airway smooth muscle cells contract while simultaneously experiencing breathing-induced stretching. Excessive stretching of cells could cause actin-myosin crosslinks, and possibly other cytoskeletal filaments, to break, thereby leading to dissipation of the prestress and inhibition of further cell stiffening. The aim of this study is to investigate the stiffening behavior of individual human airway smooth muscle (HASM) cells exposed to a combination of substrate stretching, contractile activation and relaxation. We treated cultured HASM cells with either contractile (histamine) or relaxing (DBcAMP) pharmacological agonists and used magnetic cytometry technique to investigate the stiffening behavior of these cells during uniform substrate stretching (0-30%). Cells that were not treated, as well as those treated with histamine, exhibited increasing stiffening during stretching up to 20% of substrate strain, with additional stiffening becoming inhibited for substrate strains of 20-30%. In contrast, in cells treated with DBcAMP, stretching produced moderate but continuous stiffening with increasing substrate strain. These results indicate that both active and passive components of the prestress contribute to cell stiffening. We also observed that cells permeabilized with saponin exhibited stiffening at low levels (<10%) of substrate stretching, similar to non-permeabilized cells, but not at high levels (10-30%) of stretching, where stiffening was inhibited. These data suggest that at low levels of substrate strains the relative contributions of ion channel activation as well as actin and focal adhesion remodeling are less important for stiffening than passive distension of the CSK. Taken together, our results suggest that both the active and passive components of the cytoskeletal prestress contribute to the stiffening behavior of HASM cells under physiological conditions, but that at high levels of cellular distensions there is a possible tradeoff between these two components with the contribution from the passive component becoming increasingly more important.

Cells, Cultured↗
PubMed2006

Effects of heterogeneities on the partitioning of airway and tissue properties in normal mice.

We measured the mechanical properties of the respiratory system of C57BL/6 mice using the optimal ventilation waveform method in closed- and open-chest conditions at different positive end-expiratory pressures. The tissue damping (G), tissue elastance (H), airway resistance (Raw), and hysteresivity were obtained by fitting the impedance data to three different models: a constant-phase model by Hantos et al. (Hantos Z, Daroczy B, Suki B, Nagy S, Fredberg JJ. J Appl Physiol 72: 168-178, 1992), a heterogeneous Raw model by Suki et al. (Suki B, Yuan H, Zhang Q, Lutchen KR. J Appl Physiol 82: 1349-1359, 1997), and a heterogeneous H model by Ito et al. (Ito S, Ingenito EP, Arold SP, Parameswaran H, Tgavalekos NT, Lutchen KR, Suki B. J Appl Physiol 97: 204-212, 2004). Both in the closed- and open-chest conditions, G and hysteresivity were the lowest and Raw the highest in the heterogeneous Raw model, and G and H were the largest in the heterogeneous H model. Values of G, Raw, and hysteresivity were significantly higher in the closed-chest than in the open-chest condition. However, H was not affected by the conditions. When the tidal volume of the optimal ventilation waveform was decreased from 8 to 4 ml/kg in the closed-chest condition, G and hysteresivity significantly increased, but there were smaller changes in H or Raw. In summary, values of the obtained mechanical properties varied among these models, primarily due to heterogeneity. Moreover, the mechanical parameters were significantly affected by the chest wall and tidal volume in mice. Contribution of the chest wall and heterogeneity to the mechanical properties should be carefully considered in physiological studies in which partitioning of airway and tissue properties are attempted.

Airway Resistance↗
PubMed2006

Dynamics of prestressed semiflexible polymer chains as a model of cell rheology.

We report on a model of a prestressed nonlinear semiflexible polymer chain that links thermally driven dynamics to the creep behavior of living cells. Numerical simulations show that the chain's creep follows a power law with an exponent that decreases with increasing prestress. This is related to the propagation of free energy through the chain in response to stretching, where the propagation speed is regulated by the prestress via the chain's nonlinear elasticity. These results indicate that the main aspects of cell rheology are consistent with the dynamics of single polymer chains under tension.

Actins↗
PubMed2006

Roles of stretch-activated cation channel and Rho-kinase in the spontaneous contraction of airway smooth muscle.

In guinea pigs, it is well-known that mechanical stretch of airway smooth muscle exhibits spontaneous tone which is mediated by cyclooxygenase (COX) activation. We tested the hypothesis that this spontaneous contraction of airway smooth muscle is mediated by stretch-activated non-selective cation channels and the Rho/Rho-kinase pathway, as well as COX-2 using a pharmacological approach. Isometric force and intracellular Ca(2+) concentrations ([Ca(2+)](i)) were assessed in isolated guinea pig tracheal smooth muscle tissues. The samples were stretched to a given level and the muscle behavior was monitored under isometric conditions. We observed an increase in [Ca(2+)](i) and subsequent force generation over a 15-min period. The augmented [Ca(2+)](i) and spontaneous contraction due to the stretch were markedly attenuated by application of Gd(3+), an inhibitor of stretch-activated channels, and removal of extracellular Ca(2+). In contrast, nifedipine only had a mild inhibitory effect on the contraction. (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexane-carboxamide (Y-27632; a Rho-kinase inhibitor) abolished the spontaneous contraction with no changes in [Ca(2+)](i). Simvastatin, which down-regulates Rho activity, also significantly inhibited the contraction. Moreover, indomethacin, an inhibitor of COX-1 and -2, and N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS-398; a COX-2 inhibitor) abolished the stretch-induced contraction without affecting [Ca(2+)](i), whereas the inhibitory effect of 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC560; a COX-1 inhibitor) on the contraction was much less. These findings demonstrated that Ca(2+) entry via stretch-activated channels, the Rho/Rho-kinase pathway, and COX-2 are involved in the mechanotransduction in guinea pig tracheal smooth muscle. Additionally, while the Rho/Rho-kinase pathway and COX-2 regulate the spontaneous contraction independently of [Ca(2+)](i), COX-1 is not involved in the stretch-induced force generation.

Amides↗
PubMed2006

Viscoelastic and dynamic nonlinear properties of airway smooth muscle tissue: roles of mechanical force and the cytoskeleton.

The viscoelastic and dynamic nonlinear properties of guinea pig tracheal smooth muscle tissues were investigated by measuring the storage (G') and loss (G") moduli using pseudorandom small-amplitude length oscillations between 0.12 and 3.5 Hz superimposed on static strains of either 10 or 20% of initial length. The G" and G' spectra were interpreted using a linear viscoelastic model incorporating damping (G) and stiffness (H), respectively. Both G and H were elevated following an increase in strain from 10 to 20%. There was no change in harmonic distortion (K(d)), an index of dynamic nonlinearity, between 10 and 20% strains. Application of methacholine at 10% strain significantly increased G and H while it decreased K(d). Cytochalasin D, isoproterenol, and HA-1077, a Rho-kinase inhibitor, significantly decreased both G and H but increased K(d). Following cytochalasin D, G, H, and K(d) were all elevated when mean strain increased from 10 to 20%. There were no changes in hysteresivity, G/H, under any condition. We conclude that not all aspects of the viscoelastic properties of tracheal smooth muscle strips are similar to those previously observed in cultured cells. We attribute these differences to the contribution of the extracellular matrix. Additionally, using a network model, we show that the dynamic nonlinear behavior, which has not been observed in cell culture, is associated with the state of the contractile stress and may derive from active polymerization within the cytoskeleton.

Animals↗
PubMed2006

Comparison of variable and conventional ventilation in a sheep saline lavage lung injury model.

OBJECTIVE: There has recently been considerable interest in alternative lung-protective ventilation strategies such as variable ventilation (VV). We aimed at testing VV in a large animal lung injury model and exploring the mechanism of improvement in gas exchange seen with VV. DESIGN: Randomized, controlled comparative ventilation study. SETTING: Research laboratory at a veterinary hospital. SUBJECTS: Female sheep weighing 59.8 +/- 10.57 kg and excised calf lungs. INTERVENTIONS: In a sheep saline lavage model of lung injury, we applied VV, whereby tidal volume (VT) and frequency (f) varied on each breath. Sheep were randomized into one of two groups (VV, n = 7; or control, n = 6) and ventilated for 4 hrs with all mean ventilation settings matched. MEASUREMENTS AND MAIN RESULTS: Gas exchange, lung mechanics, and hemodynamic measures were recorded over the 4 hrs. VV sheep showed improvement in gas exchange (i.e., oxygenation and carbon dioxide elimination) and ventilation pressures (i.e., reduced mean and peak airway pressures) but control sheep did not. VV sheep also displayed lower-lung elastance and mechanical heterogeneity in comparison with control sheep from 2 to 4 hrs of ventilation. To study the mechanism behind improvements seen with VV, we examined the time course associated with the enhanced recruitment occurring during VV in eight saline-lavaged excised calf lungs. We found that the recruitment associated with a larger VT during VV lasted over 200 secs, nearly an order of magnitude greater than the average time interval between large VT deliveries during VV. CONCLUSIONS: The application of VV in a large animal model of lung injury results in improved gas exchange and superior lung mechanics in comparison with CV that can be explained at least partially by the long-lasting effects of the recruitments occurring during VV.

Animals↗
PubMed2005

Risk of severe asthma episodes predicted from fluctuation analysis of airway function.

Asthma is an increasing health problem worldwide, but the long-term temporal pattern of clinical symptoms is not understood and predicting asthma episodes is not generally possible. We analyse the time series of peak expiratory flows, a standard measurement of airway function that has been assessed twice daily in a large asthmatic population during a long-term crossover clinical trial. Here we introduce an approach to predict the risk of worsening airflow obstruction by calculating the conditional probability that, given the current airway condition, a severe obstruction will occur within 30 days. We find that, compared with a placebo, a regular long-acting bronchodilator (salmeterol) that is widely used to improve asthma control decreases the risk of airway obstruction. Unexpectedly, however, a regular short-acting beta2-agonist bronchodilator (albuterol) increases this risk. Furthermore, we find that the time series of peak expiratory flows show long-range correlations that change significantly with disease severity, approaching a random process with increased variability in the most severe cases. Using a nonlinear stochastic model, we show that both the increased variability and the loss of correlations augment the risk of unstable airway function. The characterization of fluctuations in airway function provides a quantitative basis for objective risk prediction of asthma episodes and for evaluating the effectiveness of therapy.

Adult↗
PubMed2005

Relating airway diameter distributions to regular branching asymmetry in the lung.

We study the distribution Pi(n)(D) of airway diameters D as a function of generation N in asymmetric airway trees of mammalian lungs. We find that the airway bifurcations are self-similar in four species studied. Specifically, the ratios of diameters of the major and minor daughters to their parent are constants independent of N until a cutoff diameter is reached. We derive closed form expressions for Pi(N)(D) and examine the flow resistance of the tree based on an asymmetric flow division model. Our findings suggest that the observed diameter heterogeneity is consistent with an underlying regular branching asymmetry.

Animals↗
PubMed2005

Quantitative characterization of airspace enlargement in emphysema.

The mean linear intercept (L(m)) can be used to estimate the surface area for gas exchange in the lung. However, in recent years, it is most commonly used as an index for characterizing the enlargement of airspaces in emphysema and the associated severity of structural destruction in the lung. Specifically, an increase in L(m) is thought to result from an increase in airspace sizes. In this paper, we examined how accurately L(m) measures the linear dimensions of airspaces from histological sections and a variety of computer-generated test images. To this end, we developed an automated method for measuring linear intercepts from digitized images of tissue sections and calculate L(m) as their mean. We examined how the shape of airspaces and the variability of their sizes influence L(m) as well as the distribution of linear intercepts. We found that, for a relatively homogeneous enlargement of airspaces, L(m) was a reliable index for detecting emphysema. However, in the presence of spatial heterogeneities with a large variability of airspace sizes, L(m) did not significantly increase and sometimes even decreased compared with its value in normal tissue. We also developed an automated method for measuring the area and computed an equivalent diameter of each individual airspace that is independent of shape. Finally, we introduced new indexes based on the moments of diameter that we found to be more reliable than L(m) to characterize airspace enlargement in the presence of heterogeneities.

Algorithms↗
PubMed2005

Biomechanics of the lung parenchyma: critical roles of collagen and mechanical forces.

The biomechanical properties of connective tissues play fundamental roles in how mechanical interactions of the body with its environment produce physical forces at the cellular level. It is now recognized that mechanical interactions between cells and the extracellular matrix (ECM) have major regulatory effects on cellular physiology and cell-cycle kinetics that can lead to the reorganization and remodeling of the ECM. The connective tissues are composed of cells and the ECM, which includes water and a variety of biological macromolecules. The macromolecules that are most important in determining the mechanical properties of these tissues are collagen, elastin, and proteoglycans. Among these macromolecules, the most abundant and perhaps most critical for structural integrity is collagen. In this review, we examine how mechanical forces affect the physiological functioning of the lung parenchyma, with special emphasis on the role of collagen. First, we overview the composition of the connective tissue of the lung and their complex structural organization. We then describe how mechanical properties of the parenchyma arise from its composition as well as from the architectural organization of the connective tissue. We argue that, because collagen is the most important load-bearing component of the parenchymal connective tissue, it is also critical in determining the homeostasis and cellular responses to injury. Finally, we overview the interactions between the parenchymal collagen network and cellular remodeling and speculate how mechanotransduction might contribute to disease propagation and the development of small- and large-scale heterogeneities with implications to impaired lung function in emphysema.

Animals↗
PubMed2004

Mechanics, nonlinearity, and failure strength of lung tissue in a mouse model of emphysema: possible role of collagen remodeling.

Enlargement of the respiratory air spaces is associated with the breakdown and reorganization of the connective tissue fiber network during the development of pulmonary emphysema. In this study, a mouse (C57BL/6) model of emphysema was developed by direct instillation of 1.2 IU of porcine pancreatic elastase (PPE) and compared with control mice treated with saline. The PPE treatment caused 95% alveolar enlargement (P = 0.001) associated with a 29% lower elastance along the quasi-static pressure-volume curves (P < 0.001). Respiratory mechanics were measured at several positive end-expiratory pressures in the closed-chest condition. The dynamic tissue elastance was 19% lower (P < 0.001), hysteresivity was 9% higher (P < 0.05), and harmonic distortion, a measure of collagen-related dynamic nonlinearity, was 33% higher in the PPE-treated group (P < 0.001). Whole lung hydroxyproline content, which represents the total collagen content, was 48% higher (P < 0.01), and alpha-elastin content was 13% lower (P = 0.16) in the PPE-treated group. There was no significant difference in airway resistance (P = 0.7). The failure stress at which isolated parenchymal tissues break during stretching was 40% lower in the PPE-treated mice (P = 0.002). These findings suggest that, after elastolytic injury, abnormal collagen remodeling may play a significant role in all aspects of lung functional changes and mechanical forces, leading to progressive emphysema.

Animals↗
PubMed2004

Mechanical interactions between collagen and proteoglycans: implications for the stability of lung tissue.

Collagen and elastin are thought to dominate the elasticity of the connective tissue including lung parenchyma. The glycosaminoglycans on the proteoglycans may also play a role because osmolarity of interstitial fluid can alter the repulsive forces on the negatively charged glycosaminoglycans, allowing them to collapse or inflate, which can affect the stretching and folding pattern of the fibers. Hence, we hypothesized that the elasticity of lung tissue arises primarily from 1) the topology of the collagen-elastin network and 2) the mechanical interaction between proteoglycans and fibers. We measured the quasi-static, uniaxial stress-strain curves of lung tissue sheets in hypotonic, normal, and hypertonic solutions. We found that the stress-strain curve was sensitive to osmolarity, but this sensitivity decreased after proteoglycan digestion. Images of immunofluorescently labeled collagen networks showed that the fibers follow the alveolar walls that form a hexagonal-like structure. Despite the large heterogeneity, the aspect ratio of the hexagons at 30% uniaxial strain increased linearly with osmolarity. We developed a two-dimensional hexagonal network model of the alveolar structure incorporating the mechanical properties of the collagen-elastin fibers and their interaction with proteoglycans. The model accounted for the stress-strain curves observed under all experimental conditions. The model also predicted how aspect ratio changed with osmolarity and strain, which allowed us to estimate the Young's modulus of a single alveolar wall and a collagen fiber. We therefore identify a novel and important role for the proteoglycans: they stabilize the collagen-elastin network of connective tissues and contribute to lung elasticity and alveolar stability at low to medium lung volumes.

Animals↗
PubMed2004

Impact of microvascular circulation on peripheral lung stability.

The involvement of pulmonary circulation in the mechanical properties was studied in isolated rat lungs. Pulmonary input impedance (ZL) was measured at a mean transpulmonary pressure (Ptpmean) of 2 cmH2O before and after physiological perfusion with either blood or albumin. In these lungs and in a group of unperfused lungs, ZL was also measured at Ptpmean values between 1 and 8 cmH2O. Airway resistance (Raw) and parenchymal damping (G) and elastance (H) were estimated from ZL. End-expiratory lung volume (EELV) was measured by immersion before and after blood perfusion. The orientation of the elastin fibers relative to the basal membrane was assessed in additional unperfused and blood-perfused lungs. Pressurization of the pulmonary capillaries significantly decreased H by 31.5 +/- 3.7% and 18.7 +/- 2.7% for blood and albumin, respectively. Perfusion had no effect on Raw but markedly altered the Ptpmean dependences of G and H < 4 cmH2O, with significantly lower values than in the unperfused lungs. At a Ptpmean of 2 cmH2O, EELV increased by 31 +/- 11% (P = 0.01) following pressurization of the capillaries, and the elastin fibers became more parallel to the basal membrane. Because the organization of elastin fibers results in smaller H values of the individual alveolus, the higher H in the unperfused lungs is probably due to a partial alveolar collapse leading to a loss in lung volume. We conclude that the physiological pressure in the pulmonary capillaries is an important mechanical factor in the maintenance of the stability of the alveolar architecture.

Animals↗
PubMed2004

Tissue heterogeneity in the mouse lung: effects of elastase treatment.

We developed a network model in an attempt to characterize heterogeneity of tissue elasticity of the lung. The model includes a parallel set of pathways, each consisting of an airway resistance, an airway inertance, and a tissue element connected in series. The airway resistance, airway inertance, and the hysteresivity of the tissue elements were the same in each pathway, whereas the tissue elastance (H) followed a hyperbolic distribution between a minimum and maximum. To test the model, we measured the input impedance of the respiratory system of ventilated normal and emphysematous C57BL/6 mice in closed chest condition at four levels of positive end-expiratory pressures. Mild emphysema was developed by nebulized porcine pancreatic elastase (PPE) (30 IU/day x 6 days). Respiratory mechanics were studied 3 wk following the initial treatment. The model significantly improved the fitting error compared with a single-compartment model. The PPE treatment was associated with an increase in mean alveolar diameter and a decrease in minimum, maximum, and mean H. The coefficient of variation of H was significantly larger in emphysema (40%) than that in control (32%). These results indicate that PPE treatment resulted in increased time-constant inequalities associated with a wider distribution of H. The heterogeneity of alveolar size (diameters and area) was also larger in emphysema, suggesting that the model-based tissue elastance heterogeneity may reflect the underlying heterogeneity of the alveolar structure.

Airway Resistance↗
PubMed2004

Rheology of airway smooth muscle cells is associated with cytoskeletal contractile stress.

Recently reported data from mechanical measurements of cultured airway smooth muscle cells show that stiffness of the cytoskeletal matrix is determined by the extent of static contractile stress borne by the cytoskeleton (Wang N, Tolić-Nørrelykke IM, Chen J, Mijailovich SM, Butler JP, Fredberg JJ, and Stamenović D. Am J Physiol Cell Physiol 282, C606-C616, 2002). On the other hand, rheological measurements on these cells show that cytoskeletal stiffness changes with frequency of imposed mechanical loading according to a power law (Fabry B, Maksym GN, Butler JP, Glogauer M, Navajas DF, and Fredberg JJ. Phys Rev Lett 87: 148102, 2001). In this study, we examine the possibility that these two empirical observations might be interrelated. We combine previously reported data for contractile stress of human airway smooth muscle cells with new data describing rheological properties of these cells and derive quantitative, mathematically tractable, and experimentally verifiable empirical relationships between contractile stress and indexes of cell rheology. These findings reveal an intriguing role of the contractile stress: although it maintains structural stability of the cell under applied mechanical loads, it may also regulate rheological properties of the cytoskeleton, which are essential for other cell functions.

Cytoskeleton↗
PubMed2004

Microcirculatory heterogeneity in the rat small intestine during compromised flow conditions.

OBJECTIVE: To characterize and compare microcirculatory changes in the rat small intestinal tissue layers when temporal or spatial microvascular perfusion heterogeneity is present. METHODS: Intravital videomicroscopy with an orthogonal polarization spectral imaging technique was used to visualize the microcirculation of the intestinal mucosa and the longitudinal muscle during systemic (hemorrhagic shock, endotoxemia, and nitric oxide synthesis inhibition) and local (ischemia-reperfusion) circulatory disorders. The average capillary red blood cell velocity (A-RBCV) was calculated from the relative durations of the observed velocity or as a function of the perfused area, respectively. RESULTS: During hemorrhagic hypotension/resuscitation, timewise (flowmotion) and spatial heterogeneity were found to evolve in the mucosal villi and muscle layer. During resuscitation, the A-RBCV decreased by 40% in the villi and by 60% in the muscle. Reperfusion after a 30-min period of mesenteric ischemia caused a 20% reduction in A-RBCV in both layers, while endotoxin infusion caused a temporary 20% decrease in the mucosa, and a persistent, >25% decrease in the muscle. Nitric oxide synthesis inhibition resulted in spatial heterogeneity within the villi and in a 40% decrease in A-RBCV in both structures. CONCLUSIONS: Calculations of timewise variability and of heterogeneity within and between layers can be used for the comparison of distinct intramural microcirculatory changes.

Abdominal Muscles↗
PubMed2004

Flow motion in the intestinal villi during hemorrhagic shock: a new method to characterize the microcirculatory changes.

Conventional parameters are often inadequate to describe the dynamic flow changes in microcirculation. We used a novel approach to characterize oscillatory flow conditions in a canine model of hemorrhagic shock. Microcirculation in the ileal mucosal villi was visualized using intravital microscopy with the orthogonal polarization spectral imaging technique. The distribution of red blood cell velocity (RBCV) was estimated from the relative time periods of observed RBCV, and the average RBCV (A-RBCV) and its SD were then computed from the first and second moments of the RBCV distribution, respectively. Hemorrhagic shock (for 60 min) was followed by resuscitation with saline, hypertonic saline-Dextran solution (HSD, 7.2% NaCl-10% Dextran, 4 mL/kg), or HSD supplemented with the selective endothelin-A receptor antagonist ETR-p1/fl peptide (100 nmol/kg), respectively. The macrohemodynamic derangement (70% decrease in cardiac index and ileal blood flow) during shock was associated with the appearance of flow motion in the villi and an enhanced endothelin-1 release. The calculated A-RBCV was decreased by 40%. At resuscitation onset, continuous flow periods were transiently seen in 33%, 40%, and 50% of the experiments after saline, HSD, and HSD + ETR p1/fl treatment, respectively. HSD with or without endothelin-A antagonist treatment resulted in an increased relative duration of high-flow periods (by 20%) and a significant, 20% to 40% rise in A-RBCV. These results demonstrate that time-wise variability of RBCV should be used for the analysis of oscillatory flow conditions. The probabilistic estimation of A-RBCV provides a quantitative basis for comparison of the effectiveness of different resuscitation or vasoactive strategies.

Animals↗