[How I review an original scientific paper].
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Editorial Policies↗
Biomedical subjects
F G Hoppin
Publications and source records attributed to F G Hoppin.
alpha-Actin: disposition, quantities, and estimated effects on lung recoil and compliance.
We have investigated the basis and implications of pneumoconstriction by measuring disposition and quantities of alpha-smooth muscle actin in rat and guinea pig lungs and modeling its effects on lung recoil and compliance. A robust marker of contractility, alpha-smooth muscle actin appears in smooth muscle or myofibroblast-like cells in pleura, airways, blood vessels, and alveolar ductal tissues. In each site, we measured its transected area by immunofluorescent staining and frequency-modulated scanning confocal microscopy. We incorporated these data in a model of the parenchyma consisting of an extensive elastic network with embedded contractile structures. We conclude that contraction at any one of these sites alone can decrease parenchymal compliance by 20-30% during tidal breathing. This is due mostly to the stiffness of activated contractile elements undergoing passive cycling; constant muscle tension would have little effect. The magnitude of the effect corresponds with known responses of the lung to hypocapnia, consistent with a homeostatic function in which gas exchange is defended by redistributing ventilation away from overventilated units.
Actins↗
Hyperinflation and the (passive) chest wall.
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Diaphragm↗
Theoretical basis for improvement following reduction pneumoplasty in emphysema.
Reduction pneumoplasty may improve flow rates, comfort, and exercise tolerance in severe emphysema. The basis for improvement has not been systematically addressed. The major disability of emphysema stems from impairment of maximal expiratory flow-volume performance of the lung (MEFV). This requires the chest wall to operate at high volumes, which in turn severely compromises inspiratory muscle function. Clinical benefit, then, requires that MEFV performance improve so that the operating lung volume is reduced. This study presents theory and illustrative calculations. Removing nonventilating lung (e.g., bullae) simply displaces the MEFV curve down the volume axis. Removing ventilating parenchyma reduces both volume and maximal expiratory flow at iso-lung recoil pressure, and shortens the curve on the volume axis. The critical beneficial effect in both cases is reduction of the volume for a given limiting flow, VL (Vmax). Removing a given fraction of lung from the ventilating compartment is nearly as effective as removing it from the nonventilating compartment. Lowering of operating volumes benefits the strength, efficiency, endurance, and reserve of the inspiratory muscles and thus extends the metabolic scope of the emphysematous patient.
Humans↗
Variability of diaphragm structure among healthy individuals.
The ratio of the muscular cross-sectional area of the diaphragm (CSA(di)) to the axially projected area of the thorax (A(thor)) theoretically determines the strength of the inspiratory pump. We studied these dimensions in 37 healthy subjects by ultrasonography and anthropometry. In 21 subjects who did not train with weights, thickness of the diaphragm (t(di)), circumference of the rib cage (c(di)), and CSA(di) increased with height and with body weight. The increase of thoracic cavity dimensions with weight was similar to that described across a wide range of mammals and was consistent with the scaling principle of elastic similarity. CSA(di)/A(thor) showed considerable variability and was not systematically dependent on height or weight. The 15 adults who trained with weight-lifting had thicker diaphragms for comparable height and greater CSA(di)/A(thor) than the adults who did not train. We conclude that (1) the structural dimensions of the diaphragm and thorax show substantial variability, some of which is systematic with stature; (2) the variations of structure predict substantial variation of inspiratory strength which is not systematic with stature; (3) the muscular cross-section of the diaphragm is increased by general or specific training.
Adult↗
Maximal inspiratory pressures and dimensions of the diaphragm.
We postulated that the variation of maximal voluntary inspiratory pressures (PI,max and Pdi,max) among individuals largely reflects the variation of the structural attributes of the inspiratory muscles, in particular the muscular cross-sectional area of the diaphragm (CSAdi) and its axially projected area (A(thor)). To test this postulate, we measured PI,max in 36 healthy subjects, including 3 children and 15 weight-lifters, and Pdi,max in 11 subjects. Structural measurements by ultrasonography and anthropometric calipers were available as reported in the companion manuscript. We found a high degree of correlation of Pdi,max with diaphragm thickness (tdi), CSAdi, and CSAdi/A(thor) (r2 = 0.89, 0.89, and 0.77, respectively). PI,max was also correlated with diaphragm structural measurements, although less well. The weight-lifters had greater pressures, thicker diaphragms, and greater diaphragm maximal stress (sigma(max)) than adults of similar stature who had not trained with weights. We conclude (1) that both Pdi,max and PI,max reflect in part structural attributes of the respiratory muscles; (2) that the variation of maximal transdiaphragmatic pressures is largely attributable to the normal variation of diaphragm structure; (3) weight lifting increases diaphragm structure and pressures.
Adult↗
Dihedral angles of septal "bend" structures in lung parenchyma.
Alveolar parenchyma comprises two interacting tensile systems: the cable system (a network of linear condensations of connective tissue) and the membrane system (a network of quasiplanar alveolar septa). Inferences can be drawn about the mechanics of this structure from it configuration. We reported earlier (E.H. Oldmixon, J.P. Butler, and F.G. Hoppin, Jr. J. Appl. Physiol. 64: 299-307, 1988) that the angles between alveolar septa at the common three-way junctions (J) are nearly uniform, indicating that septal tensions are also nearly uniform. We now report on the interseptal angles at the next most common class of septal junction (B), a structure where two septa meet along a segment of the cable system. We find, first, that the distributions of interseptal angles at B junctions have means > 120 degrees, are narrow, and have few, if any, angles < 120 degrees. The findings of uniform 120 degrees angles at J junctions and a cutoff below 120 degrees at B junctions are also characteristic of soap films supported on a frame, which follows the physical principle of surface area minimization. We suggest that this principle may be operative in parenchymal development and remodeling.
Animals↗
Parenchymal mechanics and asthma.
The essence of asthma is impairment of expiratory flow. Expiratory flow requires lung recoil forces to supply the driving pressure and to tether the airways open. Lung recoil forces arise within the parenchymal structures, particularly the air-liquid interface and elastin. Lung recoil is mainly elastic, but shows dissipative properties and contractility, and may be changed by volume history, time dependency, and plasticity. Lung recoil tethers the airway with peribronchial forces approximating pleural pressure but the peribronchial pressure departs systematically from this when the airway constricts, ie, "interdependence." In asthma, lung recoil may decrease due to changes in surfactant, stretching of connective tissues, and growth. Parenchymal-airway coupling may be changed by local changes in parenchymal properties and particularly by swelling of the adventitia due to edema, inflammation, or matrix remodeling. Such changes in lung recoil and airway coupling may explain some of the reductions of expiratory flow seen in asthma.
Asthma↗
Semi-automated measurement of true chord length distributions and moments by video microscopy and image analysis.
The distribution of the lengths of airspace chords in pulmonary parenchyma characterizes many architectural features of the alveoli and alveolar ducts. Laborious to obtain manually, the distributions and density functions may be acquired semi-automatically by video microscopy, digitization and image processing. The accuracy of the estimation is influenced by the microscopical methods and also by the techniques used (i) to convert the digitized greyscale picture to a two-valued image, (ii) to collect the chord lengths and (iii) to compensate for finite field widths. The last problem arises because some chords are completely visible within a field while others are only partially seen, since one of the two air-tissue boundaries lies outside the field of view. This error systematically biases the observed distribution. This paper contains solutions to hardware, software and analytic problems encountered while developing the capability to measure airspace chord length density functions semi-automatically. Formulas for estimating the true chord length density function from samples of observed chord lengths are presented. Also given are formulas for the estimation of the first and second moments of the true chord length distribution from the means of observed chord lengths. These techniques of image preparation and analysis should be suitable for characterizing particle, grain or cell size distributions, especially where many profiles fall partially outside the field of view.
Animals↗
Alveolar septal folding and lung inflation history.
On the basis of microscopic appearance of excised lungs, it has been thought that alveolar septa may fold and unfold during deflation and inflation. We suspected that this appearance might depend heavily on the inflation history of the lung preparation. We therefore studied, by light and electron microscopy, dog, rabbit, and rat lungs fixed over a range of inflation pressures and after a variety of inflation histories. Septal folding, as suggested by the configurations of the air spaces, by the placement of the fine and coarse connective tissue elements, and by the pattern of infolding of alveolar epithelium, was readily seen with some inflation protocols but was absent with others. Pressure at fixation was not as important as events before fixation; deflation to 3 cmH2O did not induce folding, and inflation to 16 cmH2O did not undo the folds. This range corresponds with concepts of critical opening and closing pressures. We suggest that folds form de novo during experimental preparation; one need not postulate that septal folding was present in vivo.
Animals↗
Oxygen cost of breathing during fatiguing inspiratory resistive loads.
When a subject breathes against an inspiratory resistance, the inspiratory pressure, the inspiratory flow, and the lung volume at which the breathing task takes place all interact to determine the length of time the task can be sustained (Tlim). We hypothesized that the mechanism actually limiting tasks in which these parameters were varied involved the rate of energy utilization by the inspiratory muscles. To test this hypothesis, we studied four experienced normal subjects during fatiguing breathing tasks performed over a range of pressures and flows and at two different lung volumes. We assessed energy utilization by measuring the increment in the rate of whole body O2 consumption due to the breathing task (VO2 resp). Power and mean esophageal pressure correlated with Tlim but depended also on lung volume and inspiratory flow rate. In contrast, VO2 resp closely correlated with Tlim, and this relationship was not systematically altered by inspiratory flow or lung volume. The shape of the VO2 resp vs. Tlim curve was approximately hyperbolic, with high rates of VO2 resp associated with short endurance times and lower rates of VO2 resp approaching an asymptotic value at high Tlim. These findings are consistent with a mechanism whereby a critical rate of energy utilization determines the endurance of the inspiratory pump, and that rate varies with pressure, flow, and lung volume.
Esophagus↗
Lengths and topology of alveolar septal borders.
To clarify the mechanics of alveolar parenchyma, we undertook a stereological and topological study in perfusion-fixed canine lungs of the borders of alveolar septa. We defined the principal borders as those along which one septum 1) joins two others (J), 2) joins one other at a distinct angle (B), or 3) joins no other structure (E). E and B borders are invariably reinforced with heavy connective tissue cables; J borders are not. Relative net lengths, determined from the number of traces per section area, were J, 45%; E, 19%; and B, 25%. These were remarkably constant over 10 canine lobes (5 animals, 4 volumes). Parenchyma, then, departs from the simple models that comprise only Js and Es. Bs are important; their net length exceeds that of Es. With lobe deflation, E shortened somewhat more than required to maintain geometric similarity, suggesting that the alveolar duct contracted disproportionately. A three-dimensional reconstruction was made from serial sections, and individual border segments were followed through the reconstruction. Typical lengths of individual J, B, and E borders were nearly equal. To characterize how the network of borders were interconnected, we counted the nodes at which they meet by class, e.g., EBE for the meeting of one B, two Es. The most common are JJJJ, 26%; EEEJ, 10%; EBJ, 24%; EBE, 8%; BBJJ, 12%. If parenchyma were constructed only from free-standing entrance rings and septal junctions, only JJJJ and EEEJ would be anticipated. The presence of EBJ, EBE, and BBJJ underscores parenchymal complexity. Only 7% of septa examined were bordered entirely by Js. Connective tissue cables were not confined to the alveolar duct's lumen but often extended to the primary septa at the periphery of the ductal unit. They rarely linked adjacent alveolar ducts; only 1 in 200 cable segments crossed from one duct to another. These observations support the concept that the parenchyma is an elastic network, characterized in part by a serial mechanical linkage from connective tissue cable to septal membrane to cable again.
Animals↗
Distribution of elastin and collagen in canine lung alveolar parenchyma.
We have quantified the fibrous collagen (predominantly type I) and elastin in four locations of perceived mechanical importance: one quasi-planar feature, the alveolar septum or wall (W), and three linear features, the junction (J) of three septa, the free edges (E) of septa, and the line along which two septa join at a distinct angle or bend (B). The frequencies of these four features on light micrographs and the areas of transections through collagen and elastin seen on electron micrographs were combined to give the volumes of collagen and elastin within each feature. We find that E and B have similar compositions and contain most (4/5) of the parenchymal elastin in their relatively heavy cables. The E and B are interconnected and similar in location and composition, and they may constitute a functional entity in which elastin provides tension over a range of lung volumes, opposing septal tensions. In J and W, elastin is typically sparse and fine. Calculations, however, suggest it contributes the dominant portion of septal tension at lower lung volumes. Elastin may be essential to stabilizing septal configuration. Collagen, on the other hand, is distributed relatively evenly throughout E, B, J, and W, consistent with the role of protecting all components against rupture.
Animals↗
Chest wall distortion in patients with flail chest.
Ventilators can impose resistive and elastic loads during subject-initiated and spontaneous breaths. Such loads might worsen the chest wall distortion that is characteristic of patients with flail chest. We have tested this expectation in nine patients with flail chest and four normal subjects. All subjects breathed for 3 to 5 min on each of the following modes: assist control, intermittent mandatory ventilation (IMV), continuous positive airway pressure 5 to 10 cm H2O by demand valve and by a high flow system (CPAP-HF), and spontaneously (T-piece). Pressure at the airway opening was evaluated as a measure of ventilator loading, and magnetometric displacements of the major chest wall dimensions were evaluated to assess chest wall distortion. In contrast to the normal volunteers, patients with flail chest displayed chest wall distortion during active inspirations. The patterns of distortion were variable among patients. The degree of distortion varied among ventilator modes; generally, there was a greater degree of chest wall distortion in breaths with greater loading. For example, distortion was greater during the spontaneous breaths taken on the IMV-mode than during spontaneous breaths taken on the T-piece. The CPAP-HF mode resulted in the least distortion, reversing chest wall distortion in five patients, improving it in two, and not changing the distortion in the remaining two. The improvements may be related to positive pleural pressures and to the minimal ventilator-imposed load of the high gas flow system. The distortion imposed by ventilators increases the work of breathing in these patients and may thus contribute to difficulty in weaning.
Aged↗
Dihedral angles between alveolar septa.
To determine the dihedral angle, alpha, at the characteristic three-way septal junctions of lung parenchyma, we examined photomicrographs of sections. The three angles, A, formed where three septal traces meet on section, were measured and found to range between approximately 50 and 170 degrees. Theoretical considerations predicted that the dispersion of alpha is much narrower than that of A. The mean of A and alpha is identically 120 degrees. The standard deviation of alpha was inferred from the cumulative distribution function of A. In lungs inflated to 30 cmH2O (VL30), the standard deviation of alpha was very small (approximately 2 degrees) and increased to approximately 6 degrees in lungs inflated to 0.4 VL30. These findings imply that at VL30 tensions exerted by septa are locally homogeneous (2% variation) and at lower lung volumes become less so (6% variation). At high distending pressures, tissue forces are thought to dominate interfacial forces, and therefore the local uniformity of tensions suggests a stress-responsive mechanism for forming or remodeling the connective tissues. The source of the local nonuniformity at lower volumes is unclear but could relate to differences in mechanical properties of alveolar duct and alveoli. Finally, local uniformity does not imply global uniformity.
Animals↗
Increased lung volume limits endurance of inspiratory muscles.
We examined the influence of lung volume on the ability of normal subjects to sustain breathing against inspiratory resistive loading. Four normal subjects breathed on a closed circuit in which inspiration was loaded by a flow resistor. Subjects were assigned a series of breathing tasks over a range of pressures and flows. In each task there was a specified resistor and also targets for either mean esophageal or airway opening pressure, respiratory frequency, and duty cycle. Endurance was assessed as the length of time to failure of the assigned task. The prime experimental variable was lung volume, which was increased by approximately 1 liter during some tasks; 8 cmH2O continuous positive airway pressure was applied to increase lung volume without increasing elastic load. As previously shown (McCool et al.J. Appl. Physiol. 60: 299-303, 1986), for tasks that could be sustained for the same time, there was an inverse linear relationship of mean esophageal pressure with inspiratory flow rate. This trade-off of pressure and flow was apparent both with and without the increase of lung volume. Comparable tasks, however, could not be sustained as long at the higher lung volumes. This effect of volume on endurance was greater for tasks characterized by high inspiratory pressures and low flow rates than for tasks that could be sustained for the same time but that had lower inspiratory pressures and higher flow rates. This is probably due to the effects of shortening of the sarcomere on fatiguability. Increased lung volume, per se, may contribute to respiratory failure because of increased inspiratory muscle fatiguability by mechanisms independent of elastic load.
Airway Resistance↗
Respiratory muscle dysfunction in Parkinson's disease.
Patients with Parkinson's disease may have more difficulty performing repetitive motor acts than single motor acts because of bradykinesia and skeletal muscle rigidity. We thought that repetitive ventilatory tasks might be similarly limited and that this dysfunction would likely contribute to respiratory muscle fatigue. We studied 9 patients with Parkinson's disease who had no evidence of restrictive or obstructive lung disease and 5 normal age-matched control subjects who performed repetitive, forced inspiratory resistive-loaded tasks. The time a given mean airway opening pressure could be sustained, the incremental oxygen cost of breathing, and the work rate of breathing (W) were measured. Although maximal static inspiratory pressures were comparable in both groups, 8 of the 9 patients could not sustain as high a W in the resistive-loaded tasks as could the normal control subjects (41.0 +/- 23.0 versus 67.7 +/- 29.1 J/min; mean +/- SD, p less than 0.01) and the efficiency of breathing was reduced (2.0 +/- 0.8 versus 3.8 +/- 1.4%; p less than 0.01). These findings are similar to derangements of task performance by peripheral skeletal muscle groups in Parkinson's disease.
Aged↗
Pressure-flow effects on endurance of inspiratory muscles.
We examined the effects of varying inspiratory pressures and flows on inspiratory muscle endurance. Four normal subjects performed voluntary forced breathing with various assigned inspiratory tasks. Duty cycle, tidal volume, and mean lung volume were the same in all tasks. Mean esophageal pressure, analogous to a pressure-time integral (PTes), was varied over a wide range. In each task the subject maintained an assigned PTes while breathing on one of a range of inspiratory resistors, and this gave a range of inspiratory flows at any given PTes. Inspiratory muscle endurance for each task was assessed by the length of time the task could be maintained (Tlim). For a given resistor, Tlim increased as PTes decreased. At a given PTes, Tlim increased as the external resistance increased and therefore as mean inspiratory flow rate (VI) decreased. Furthermore, for a given Tlim, PTes and VI were linearly related with a negative slope. We conclude that inspiratory flow, probably because of its relationship to the velocity of muscle shortening, is an independent variable importantly influencing endurance of the inspiratory muscles.
Adult↗