Impaired lung compliance and DL,CO but no restrictive ventilatory defect in sarcoidosis.

Sarcoidosis is a systemic granulomatous disease with predominant manifestation in the lungs, often presenting as interstitial lung disease. Pulmonary function abnormalities in sarcoidosis include restriction of lung volumes, reduction in diffusing capacity of the lung for carbon monoxide (D(L,CO)), reduced static lung compliance (C(L,s)) and airway obstruction. The aim of the present study was to assess various lung function indices, including C(L,s) and D(L,CO), as markers of functional abnormality in sarcoidosis patients. Results from 830 consecutive patients referred for lung function tests with a diagnosis of sarcoidosis (223 in stage I, 486 in stage II and 121 in stage III) were retreospectively analysed. The mean ± sd age of the patients was 40 ± 11 yrs; 18% were active smokers and 24% were former smokers. Normal total lung capacity was found in 772 (93%) patients. Of these cases, 24.5% had a low C(L,s) and 21.5% had a low D(L,CO). At least one abnormality was observed in 39.3% of these patients, whereas, in restrictive patients, this figure was 88%. Airway obstruction was present in 11.7% of cases. Lung volumes usually remain within the normal range and measurement of either C(L,s) or D(L,CO) often reveal impaired lung function in sarcoidosis patients, even when their lung volumes are still in the normal range; these two measurements provide complementary information.

Effects of age on elastic moduli of human lungs.

The model of the lung as an elastic continuum undergoing small distortions from a uniformly inflated state has been used to describe many lung deformation problems. Lung stress-strain material properties needed for this model are described by two elastic moduli: the bulk modulus, which describes a uniform inflation, and the shear modulus, which describes an isovolume deformation. In this study we measured the bulk modulus and shear modulus of human lungs obtained at autopsy at several fixed transpulmonary pressures (Ptp). The bulk modulus was obtained from small pressure-volume perturbations on different points of the deflation pressure-volume curve. The shear modulus was obtained from indentation tests on the lung surface. The results indicated that, at a constant Ptp, both bulk and shear moduli increased with age, and the increase was greater at higher Ptp values. The micromechanical basis for these changes remains to be elucidated.

Evaluation of pulmonary resistance and maximal expiratory flow measurements during exercise in humans.

To evaluate methods used to document changes in airway function during and after exercise, we studied nine subjects with exercise-induced asthma and five subjects without asthma. Airway function was assessed from measurements of pulmonary resistance (RL) and forced expiratory vital capacity maneuvers. In the asthmatic subjects, forced expiratory volume in 1 s (FEV1) fell 24 +/- 14% and RL increased 176 +/- 153% after exercise, whereas normal subjects experienced no change in airway function (RL -3 +/- 8% and FEV1 -4 +/- 5%). During exercise, there was a tendency for FEV1 to increase in the asthmatic subjects but not in the normal subjects. RL, however, showed a slight increase during exercise in both groups. Changes in lung volumes encountered during exercise were small and had no consistent effect on RL. The small increases in RL during exercise could be explained by the nonlinearity of the pressure-flow relationship and the increased tidal breathing flows associated with exercise. In the asthmatic subjects, a deep inspiration (DI) caused a small, significant, transient decrease in RL 15 min after exercise. There was no change in RL in response to DI during exercise in either asthmatic or nonasthmatic subjects. When percent changes in RL and FEV1 during and after exercise were compared, there was close agreement between the two measurements of change in airway function. In the groups of normal and mildly asthmatic subjects, we conclude that changes in lung volume and DIs had no influence on RL during exercise. Increases in tidal breathing flows had only minor influence on measurements of RL during exercise. Furthermore, changes in RL and in FEV1 produce equivalent indexes of the variations in airway function during and after exercise.

Experimental emphysema.

This animal model of emphysema exhibits the same abnormalities in respiratory mechanics as those seen in human emphysema. The histologic and radiographic findings also closely resemble changes of panacinar disease. Moreover, the progressive hypoxemia preceding hypercarbia also parallels the clinical course seen in human disease. Drawbacks of this model include the long time period required to develop significant changes and the cost of maintaining the animals for such a time period. Large cystic areas were not noted in our animals and one would have to turn to another model to address the problem of giant bullous emphysema. There is no ideal animal model of pulmonary emphysema, and the usefulness of an experimental model should be judged on how well it answers the specific questions. Significant information has been obtained using various animal models of emphysema in lung transplantation, diaphragmatic function, pulmonary hemodynamics, and in several other areas. The dog appears to be a suitable model for thoracic surgical research on emphysema.

Respiratory muscle strength in the elderly. Correlates and reference values. Cardiovascular Health Study Research Group.

Maximal inspiratory pressure (MIP) was assessed in 4,443 ambulatory participants of the Cardiovascular Health Study, 65 yr of age and older, sampled from four communities. Maximal expiratory pressure (MEP) was also measured in 790 participants from a single clinic. Positive predictors of MIP included male sex, FVC, handgrip strength, and higher levels of lean body mass (or low bioelectric resistance). Negative predictors were age, current smoking, self-reported fair to poor general health, and waist size. Both participant and technician learning effects were noted, but there was no independent effect of race, hypertension, cardiovascular disease, or diabetes. A healthy subgroup was identified by excluding current smokers, those with fair to poor general health, or an FEV1 less than 65% of predicted. Mean values determined from the healthy group were 57/116 cm H2O (MIP/MEP) for women, and 83/174 for men. Lower limits of the normal range (fifth percentiles) were 45 to 60% of the mean predicted values. The reference equations derived from this group of healthy 65 to 85-yr-olds may be used by pulmonary function laboratories and respiratory therapists who evaluate the respiratory muscle strength of elderly patients.

Pulmonary mechanics in lymphangioleiomyomatosis.

Standard pulmonary function and mechanics studies were done in eight female patients with lymphangioleiomyomatosis diagnosed by open-lung biopsy. Five patients were studied before hormone treatment. The mean age of the patients was 40 +/- 3 (SEM) years. Two of the eight had a smoking history of 10 pack-years or more, but all had quit smoking several years before evaluation. There was a trend toward increased total lung capacity (114 +/- 7% expressed as mean of percentage predicted +/- SEM) and increased residual volume (207 +/- 24%). Of the eight patients seven had expiratory obstruction as evidenced by the reduced forced expiratory volume in 1 s/forced vital capacity ratio [( FEV1/FVC] 61 +/- 6%). Steady-state diffusing capacity for carbon monoxide was reduced in seven of the patients (57 +/- 12%). Pulmonary mechanics studies performed in a body plethysmograph revealed a modest reduction in retractive force both at total lung capacity and at 90% total lung capacity (67 +/- 10 and 59 +/- 9%, respectively). Static compliance tended to be increased (128 +/- 19%). Pulmonary flow resistance was markedly elevated (266 +/- 46%). Maximal flow-static recoll curves revealed that in the seven patients with expiratory obstruction the cause was predominantly airway narrowing rather than loss of lung elastic forces. We conclude that in this group of patients with lymphangioleiomyomatosis there was no evidence for significant restriction. Although there was some decrease in retractive force consistent with emphysema, expiratory flows were reduced predominantly because of airway narrowing or obstruction rather than loss of pulmonary elastic recoil forces.

Pressure-volume curves in smokers. Comparison with alpha-1-antitrypsin deficiency.

The diagnosis of emphysema has been associated with changes in the appearance of the pressure-volume (P-V) curve: reduced maximal recoil pressure, increased lung volume, and a shift in the position of the curve to the left. In our clinical practice, we have observed that patients with chronic obstructive lung disease (COPD) commonly had P-V curves with reduced maximal elastic recoil that are difficult to classify according to the classic description of the P-V curve in emphysema. In order to study the variability of P-V curves, we studied 39 cigarette smokers attending a pulmonary clinic (age, 61 +/- 1 yr; smoking history, 45 +/- 3 pack-years; mean +/- SEM) and compared them with 20 patients with alpha-1-antitrypsin deficiency (AATD) (age, 41 +/- 2 yr; 13 smokers with a smoking history of 17 +/- 2 pack-years, and seven nonsmokers). Subjects underwent spirometry, lung volume, and diffusing capacity measurements as well as static deflation P-V curves. To characterize the P-V curves, we used transpulmonary pressure at 90% of TLC (PL90) as a measure of overall recoil and specific compliance (Csp) as a measure of the slope of the initial part of the P-V curve. The curves of non-AATD smokers were classified into three groups: 13 had PL90 greater than or equal to 80% predicted (Group I), 13 had PL90 less than 80% predicted and Csp greater than or equal to 0.08 (Group II), and 13 had PL90 less than 80% predicted and Csp less than 0.08 (Group III).(ABSTRACT TRUNCATED AT 250 WORDS)

Carbon monoxide diffusing capacity of the lungs determined by single-breath and steady-state exercise methods.

We measured carbon monoxide diffusing capacity of the lungs (DL,CO) by both the resting single-breath (SB) and steady-state (SS) exercise methods in 95 patients referred for pulmonary function testing. A 10-second breath-holding method was used for the SB test. DL,CO (SS) was measured during the last minute of a 3-minute exercise test on a 9-inch step. Results of the two methods showed good agreement, the SB-SS difference averaging -0.70 (SD, 3.39) ml/min per mm Hg. The difference between the two methods was not correlated with other measurements of pulmonary function except minute ventilation during the exercise performed in the DL,CO (SS) procedure. In a separate study of laboratory personnel, the day-to-day variabilities of the two tests were similar (SD, 1.4 ml/min per mm Hg). Alveolar volume obtained by helium dilution during the SB test was comparable to total lung capacity (TLC) estimated by multiple-breath nitrogen washout in patients without severe airway obstruction. In severe airway obstruction, the mean SB alveolar volume was 13.8% less than the TLC by nitrogen washout, a difference that may be useful as an indicator of inefficiency of gas mixing in the lungs. We conclude that the SB and SS exercise methods provide similar estimates of DL,CO in patients referred to a pulmonary function laboratory.

Parenchymal interdependence and airway response to methacholine in excised dog lobes.

The objective of this investigation was to determine the minimum transpulmonary pressure (PL) at which the forces of interdependence between the airways and the lung parenchyma can prevent airway closure in response to maximal stimulation of the airways in excised canine lobes. We first present an analysis of the relationship between PL and the transmural pressure (Ptm) that airway smooth muscle must generate to close the airways. This analysis predicts that airway closure can occur at PL less than or equal to 10 cmH2O with maximal airway stimulation. We tested this prediction in eight excised canine lobes by nebulizing 50% methacholine into the airways while the lobe was held at constant PL values ranging from 25 to 5 cmH2O. Airway closure was assessed by comparing changes in alveolar pressure (measured by an alveolar capsule technique) and pressure at the airway opening during low-amplitude oscillations in lobar volume. Airway closure occurred in two of the eight lobes at PL = 10 cmH2O; in an additional five it occurred at PL = 7.5 cmH2O. We conclude that the forces of parenchymal interdependence per se are not sufficient to prevent airway closure at PL less than or equal to 7.5 cmH2O in excised canine lobes.

Characteristics of tachyphylaxis to inhaled histamine in anesthetized dogs.

Three consecutive dose-response curves to aerosolized histamine were obtained in 11 anesthetized dogs. All dogs showed desensitization (i.e., tachyphylaxis) to high doses of histamine. Tachyphylaxis was highly reproducible. No tachyphylaxis occurred with inhaled acetylcholine or methacholine. Beta-Adrenergic blockade with propranolol or muscarinic blockade with atropine given intravenously had no effect on the histamine tachyphylaxis. Duration of thiamylal anesthesia did not alter the histamine responsiveness. Histamine tachyphylaxis was also seen with chloralose-urethan anesthesia. Since tachyphylaxis is not observed with acetylcholine, it cannot be attributed to a general decline in muscle contractility. We conclude that histamine tachyphylaxis in vivo is not explained by effects of cholinergic reflexes, catecholamine release, duration of anesthesia, or, probably, type of anesthetic agent.

Histamine tachyphylaxis in canine airways despite prostaglandin synthesis inhibition.

Tachyphylaxis to aerosolized histamine was studied in dogs anesthetized with thiamylal after pretreatment with prostaglandin synthesis inhibitors. Three consecutive histamine dose-response curves were obtained in nine dogs pretreated with 5 mg/kg indomethacin; two of these nine were also pretreated with 10 mg/kg indomethacin. Seven of the nine dogs were pretreated with 4 mg/kg sodium meclofenamate; four of these seven were also pretreated with 12 mg/kg. All dogs had tachyphylaxis at high concentrations of histamine regardless of inhibitor used. Pretreatment with indomethacin while the dogs were under alpha-chloralose-urethan anesthesia gave similar results. Histamine tachyphylaxis was also studied both in the presence and in the absence of indomethacin in tracheal smooth muscle strips obtained from seven additional dogs. A decrease in the median effective dose to histamine was observed in the indomethacin-treated strips, but tachyphylaxis to histamine remained. We conclude that prostaglandin synthesis inhibition does not reverse histamine tachyphylaxis either in vivo or in vitro. Thus the mechanism of histamine tachyphylaxis remains unexplained.

Evaluation of the contribution of tannin to the acute pulmonary inflammatory response against inhaled cotton mill dust.

Anesthetized, intubated, and mechanically ventilated rabbits were exposed to aerosolized saline, cotton dust extract (CDE), or tannin for 5 minutes and lavaged 4 hours after exposure. Cell numbers and types present in the bronchoalveolar lavage fluid (BALF) were determined and the concentrations of thromboxane A2 (TxA2) and prostaglandin F2-alpha (PGF2-alpha) in the BALF were also analyzed. The saline control animals had increased numbers and percentage of polymorphonuclear leukocytes (PMN) in the BALF as well as increased levels of TxB2 and PGF2-alpha compared with unexposed animals. Exposure to CDE further increased the number and percentage of PMN and the level of PGF2-alpha but had no effect on TxA2 levels when compared with control animals. Tannin exposure increased PGF2-alpha levels to the same extent as CDE exposure. PMN also increased but to a lesser extent than with CDE. These results indicate that the inflammatory response to CDE is only partially due to the tannin present in CDE.

Inhomogeneity during deflation of excised canine lungs. I. Alveolar pressures.

Factors both intrinsic and extrinsic to the lung may cause inhomogeneity of alveolar pressures during deflation. Wilson et al. (J. Appl. Physiol. 59: 1924-1928, 1985) predicted that any such inhomogeneity would be limited by interdependence of regional expiratory flows. To test this hypothesis and to explore how the pleural pressure gradient might affect inhomogeneity of alveolar pressures, we deflated at submaximal flows excised canine lobes that first were suspended in air and then were immersed in foams that simulated the vertical gradient of pleural pressure. Interregional inhomogeneity of regional transpulmonary pressures was measured with use of an alveolar capsule technique. Flow-dependent inhomogeneity of alveolar pressures was present, with differences in alveolar pressure quickly relaxing to a constant limiting value at each flow. Foam immersion increased inhomogeneity at a given flow. We conclude that factors intrinsic to the lung cause significant inhomogeneity of alveolar pressures at submaximal expiratory flows and that this inhomogeneity is enhanced by the extrinsic gradient of pleural pressure. These observations are consistent with the interdependence of flow proposed by Wilson et al.

Inhomogeneity during deflation of excised canine lungs. II. Alveolar volumes.

We have previously demonstrated appreciable inhomogeneity of alveolar pressures measured by a capsule technique in excised canine lobes deflated at submaximal flows (J. Appl. Physiol. 65: 1757-1765, 1988). We further analyzed the results of these experiments by estimating alveolar volumes (VA) and regional flows from regional transpulmonary pressures, assuming that regional pressure-volume relationships were homogeneous. Deflation at submaximal flows of lungs suspended in air caused significant flow-dependent inhomogeneity of VA that increased as lung volume decreased. Immersion of lungs in stable foams that simulated the gradient of pleural pressure modified the pattern of emptying, but not always to a gravity-dependent sequence. Limitation of regional expiratory flow was often asynchronous during both air suspension and foam immersion. There was no evidence of a common regional flow-volume curve. Submaximal deflation is a complex heterogeneous process, with the interregional pattern of emptying determined by the interaction of factors that are both intrinsic and extrinsic to the lungs.

Inhomogeneity during deflation of excised canine lungs. III. Single-breath O2 tests.

Both interregional and intraregional mechanisms may cause changes in N2 concentration of expired gas during the phases of the single-breath O2 test (SBO2) that follow dead-space washout. To evaluate the possible importance of each mechanism, we performed the SBO2 in excised canine lungs that were first suspended in air and then immersed in stable foams that simulated the vertical gradient of pleural pressure. The lungs were deflated at constant submaximal flows. The slope of phase III diminished with increasing expiratory flow and increased with foam immersion. The onset of phase IV depended on flow, and a terminal decrease in N2 concentration (phase V) was often observed. Simultaneously measured estimates of regional flows and volumes (J. Appl. Physiol. 65: 1764-1774, 1988) were used to further interpret these results. The onset of phase IV at flows greater than quasi-static signified the onset of flow limitation of dependent regions. The onset of phase V corresponded to flow limitation of nondependent regions.

Regional ventilation in excised lobes exposed to a transpulmonary pressure gradient.

We performed the quasi-static single-breath oxygen test (SBO2) in 16 excised canine lower lung lobes while the lobes were first suspended in air and then later immersed in stable foams that provided a vertical transpulmonary pressure gradient. In lobes suspended in air, an approximately linear alveolar plateau (AP) was obtained. The AP during foam immersion was markedly curvilinear, with phase IV seen at end expiration. The observed AP during foam immersion could be predicted by a mathematical model that assumed a homogeneous transpulmonary pressure-regional volume relationship equal to the overall pressure-volume (PV) relationship measured with the lobe suspended in air. The accuracy of this model was further confirmed by measuring the washout of nitrogen injected into different lung regions through alveolar capsules. We also used the model to examine the relationship between the onset of dependent airway closure and two of its proposed indicators: the onset of phase IV and the inflection point of the overall PV relationship. In most lobes, the lung volume at the onset of phase IV was less than the modeled lung volume at dependent airway closure. The lung volume at the inflection point was always less than the modeled lung volume at dependent airway closure. We show that the overall PV relationship measured in lobes suspended in air provides an accurate estimate of regional PV relationships during foam immersion.

Canine model of chronic bronchial injury. Lung mechanics and pathologic changes.

Bronchial injury was induced in 7 dogs by exposure to nebulized 1% nitric acid 3 days per week for 4 weeks. Lung mechanics were measured prior to exposure, at the completion of exposure, and at 1, 3, and 5 months postexposure. Airway obstruction persisted unabated throughout the postexposure period, with significant reductions in maximal expiratory flows. Pulmonary resistance, the slope of phase III, and the volume of isoflow were increased. Hyperresponsiveness to histamine developed between 3 and 5 months. Histologically, there was minimal damage to the cartilaginous airways. Widespread chronic inflammation with minimal fibrosis was seen in the membranous bronchi and respiratory bronchioles. Pathology scores for cartilaginous and noncartilaginous (small) airways were developed and correlated with tests of airway function. Small airways pathology scores correlated with flows at 50 and 25% of the vital capacity and with pulmonary resistance. Density dependence of maximal expiratory flow, closing volume, and closing capacity failed to correlate with either the airway obstruction or the small airways pathology scores.

Effect of effort on measurement of forced expiratory volume in one second.

The American Thoracic Society recommends that the largest FEV1 be reported from a set of forced expiratory vital capacity maneuvers performed with maximal expiratory effort. However, increased expiratory effort can decrease the FEV1. When we evaluated the peak expiratory flow rate (PEFR) in 5 normal subjects, measured from flow-volume curves, as a noninvasive index of expiratory effort, it was positively correlated with indices of effort obtained by using an esophageal balloon. We then measured the difference (dFEV1)between the largest FEV1 and FEV1 from the maneuver with the highest PEFR during 10 test sessions in 10 normal subjects. Thus, dFEV1 was always greater than or equal to 0. The mean dFEV1 was 110 ml for all sessions but decreased to 80 ml when maneuvers with poorly reproducible PEFR or forced expiratory vital capacity values were discarded. We also reviewed 9.471 spirometry sessions from outpatients and found dFEV1 to be greater than 50 ml in 26% of this population and greater than 151 ml in 7%. We concluded that during standard spirometry, FEV1 is inversely dependent on effort. Maximal effort decreases FEV1 because of the effect of thoracic gas compression on lung volume. We recommend that values from spirometry maneuvers that demonstrate submaximal effort, indicated by a decreased PEFR, be discarded. The flow-volume curve display of superimposed efforts facilitates the recognition of submaximal efforts.

Discharge of abdominal muscle alpha and gamma motoneurons during expiratory loading in cats.

Expiratory responses were elicited in abdominal alpha and gamma motoneurons of anesthetized cats by continuous positive airway pressure, tracheal occlusion, lung inflation, or step-changes in expiratory airflow resistance. Abdominal alpha motoneurons were silent during quiet breathing but became rhythmically active whenever expiration was opposed. In addition, the responses of abdominal alpha motoneurons to an increase in expiratory airflow resistance included an increase in discharge frequency, an earlier firing time of individual neurons, recruitment of successively larger motor fibers, and an increased duration of discharge. Abdominal gamma motoneurons discharged continuously during quiet breathing and an increased frequency of discharge during the expiratory phase of the respiratory cycle was evident in approximately one-third of the fibers. This respiratory modulation was enhanced, or initiated if absent, by imposing a load during expiration. Bilateral cervical vagotomy abolished both the respiratory modulation of abdominal gamma motoneurons and expiratory activity in abdominal alpha motoneurons indicating the importance of supraspinal structures. Coactivation of abdominal alpha and gamma motoneurons during active expiration also suggests that a segmental reflex involving abdominal muscle spindles may be capable of providing automatic compensation for changes in expiratory load. In conclusion, both vagal and dorsal root information appear to contribute to the proprioceptive control of abdominal muscle expiratory activity.