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.     

Correlated Variability in the Breathing Pattern and End-Expiratory Lung Volumes in Conscious Humans

In order to characterize the variability and correlation properties of spontaneous breathing in humans, the breathing pattern of 16 seated healthy subjects was studied during 40 min of quiet breathing using opto-electronic plethysmography, a contactless technology that measures total and compartmental chest wall volumes without interfering with the subjects breathing. From these signals, tidal volume (V_T), respiratory time (T_TOT) and the other breathing pattern parameters were computed breath-by-breath together with the end-expiratory total and compartmental (pulmonary rib cage and abdomen) chest wall volume changes. The correlation properties of these variables were quantified by detrended fluctuation analysis, computing the scaling exponentα. V_T, T_TOT and the other breathing pattern variables showed α values between 0.60 (for minute ventilation) to 0.71 (for respiratory rate), all significantly lower than the ones obtained for end-expiratory volumes, that ranged between 1.05 (for rib cage) and 1.13 (for abdomen) with no significant differences between compartments. The much stronger long-range correlations of the end expiratory volumes were interpreted by a neuromechanical network model consisting of five neuron groups in the brain respiratory center coupled with the mechanical properties of the respiratory system modeled as a simple Kelvin body. The model-based α for V_T is 0.57, similar to the experimental data. While the α for T_TOT was slightly lower than the experimental values, the model correctly predicted α for end-expiratory lung volumes (1.045). In conclusion, we propose that the correlations in the timing and amplitude of the physiological variables originate from the brain with the exception of end-expiratory lung volume, which shows the strongest correlations largely due to the contribution of the viscoelastic properties of the tissues. This cycle-by-cycle variability may have a significant impact on the functioning of adherent cells in the respiratory system.     

Letters to the Editor

The following is the abstract of the article discussed inthe subsequent letter:

Yuan, Huichin, Edward P. Ingenito, and BélaSuki. Dynamic properties of lung parenchyma: mechanicalcontributions of fiber network and interstitial cells. J. Appl.Physiol. 83(5): 1420-1431, 1997.We investigated thecontributions of the connective tissue fiber network and interstitialcells to parenchymal mechanics in a surfactant-free system. In eightstrips of uniform dimension from guinea pig lung, we assessed thestorage (G') and loss (G") moduli by using pseudo-random lengthoscillations containing a specially designed set of seven frequenciesfrom 0.07 to 2.4 Hz at baseline, during methacholine (MCh) challenge,and after death of the interstitial cells. Measurements were made atmean forces of 0.5 and 1 g and strain amplitudes of 5, 10, and 15% andwere repeated 12 h later in the same, but nonviable samples. Theresults were interpreted using a linear viscoelastic modelincorporating both tissue damping (G) and stiffness (H). The G' and G"increased linearly with the logarithm of frequency, and both G and Hshowed negative strain amplitude and positive mean force dependence. After MCh challenge, the G' and G" spectra were elevated uniformly, andG and H increased by <15%. Tissue stiffness, strain amplitude, andmean force dependence were virtually identical in the viable andnonviable samples. The G and hence energy dissipation were ~10%smaller in the nonviable samples due to absence of actin-myosin cross-bridge cycling. We conclude that the connective tissue network may also dominate parenchymal mechanics in the intact lung, which canbe influenced by the tone or contraction of interstitial cells.

     

Selected contribution: airway caliber in healthy and asthmatic subjects: effects of bronchial challenge and deep inspirations.

In 9 healthy and 14 asthmatic subjects before and after a standard bronchial challenge and a modified [deep inspiration (DI), inhibited] bronchial challenge and after albuterol, we tracked airway caliber by synthesizing a method to measure airway resistance (Raw; i.e., lung resistance at 8 Hz) in real time. We determined the minimum Raw achievable during a DI to total lung capacity and the subsequent dynamics of Raw after exhalation and resumption of tidal breathing. Results showed that even after a bronchial challenge healthy subjects can dilate airways maximally, and the dilation caused by a single DI takes several breaths to return to baseline. In contrast, at baseline, asthmatic subjects cannot maximally dilate their airways, and this worsens considerably postconstriction. Moreover, after a DI, the dilation that does occur in airway caliber in asthmatic subjects constricts back to baseline much faster (often after a single breath). After albuterol, asthmatic subjects could dilate airways much closer to levels of those of healthy subjects. These data suggest that the asthmatic smooth muscle resides in a stiffer biological state compared with the stimulated healthy smooth muscle, and inhibiting a DI in healthy subjects cannot mimic this.     

Input impedance and peripheral inhomogeneity of dog lungs.

Tracheal pressure, central airflow, and alveolar capsule pressures in cardiac lobes were measured in open-chest dogs during 0.1- to 20-Hz pseudorandom forced oscillations applied at the airway opening. In the interval 0.1-4.15 Hz, the input impedance data were fitted by four-parameter models including frequency-independent airway resistance and inertance and tissue parts featuring a marked negative frequency dependence of resistance and a slight elevation of elastance with frequency. The models gave good fits both in the control state and during histamine infusion. At the same time, the regional transfer impedances (alveolar pressure-to-central airflow ratios) showed intralobar and interlobar variabilities of similar degrees, which increased with frequency and were exaggerated during histamine infusion. Results of simulation studies based on a lung model consisting of a central airway and a number of peripheral units with airway and tissue parameters that were given independent wide distributions were in agreement with the experimental findings and showed that even an extremely inhomogeneous lung structure can produce virtually homogeneous mechanical behavior at the input.     

Design of a Novel Equi-Biaxial Stretcher for Live Cellular and Subcellular Imaging

Cells in the body experience various mechanical stimuli that are often essential to proper cell function. In order to study the effects of mechanical stretch on cell function, several devices have been built to deliver cyclic stretch to cells; however, they are generally not practical for live cell imaging. We introduce a novel device that allows for live cell imaging, using either an upright or inverted microscope, during the delivery of cyclic stretch, which can vary in amplitude and frequency. The device delivers equi-biaxial strain to cells seeded on an elastic membrane via indentation of the membrane. Membrane area strain was calibrated to indenter depth and the device showed repeatable and accurate delivery of strain at the scale of individual cells. At the whole cell level, changes in intracellular calcium were measured at different membrane area strains, and showed an amplitude-dependent response. At the subcellular level, the mitochondrial network was imaged at increasing membrane area strains to demonstrate that stretch can lead to mitochondrial fission in lung fibroblasts. The device is a useful tool for studying transient as well as long-term mechanotransduction as it allows for simultaneous stretching and imaging of live cells in the presence of various chemical stimuli.     

Effects of collagenase and elastase on the mechanical properties of lung tissue strips

The dynamic stiffness (H), dampingcoefficient (G), and harmonic distortion (k_d)characterizing tissue nonlinearity of lung parenchymal strips fromguinea pigs were assessed before and after treatment with elastase orcollagenase between 0.1 and 3.74 Hz. After digestion, data wereobtained both at the same mean length and at the same mean force of thestrip as before digestion. At the same mean length, G and H decreasedby ~33% after elastase and by ~47% after collagenase treatment.At the same mean force, G and H increased by ~7% after elastase andby ~25% after collagenase treatment. The k_dincreased more after collagenase (40%) than after elastase (20%)treatment. These findings suggest that, after digestion, the fractionof intact fibers decreases, which, at the same mean length, leads to adecrease in moduli. At the same mean force, collagen fibers operate ata higher portion of their stress-strain curve, which results in anincrease in moduli. Also, G and H were coupled so that hysteresivity(G/H) did not change after treatments. However,k_d was decoupled from elasticity and wassensitive to stretching of collagen, which may be of value in detectingstructural alterations in the connective tissue of the lung.