The purpose of this study was to compare the dimensions of the peripheral airways in fatal asthma with those from patients with nonfatal asthma, mild COPD, and normal lung function. Lung specimens from eight individuals who had fatal asthmatic attacks were obtained at postmortem and compared with similar specimens from three asthmatic patients who died of an unrelated cause and four specimens obtained from known asthmatic patients who required lung resection for tumor. These 15 asthmatic lungs were also compared with lungs resected for peripheral neoplasms from 15 patients with normal airway function (FEV1, % of predicted > 85) and 15 patients with mild chronic airflow obstruction (FEV1, % of predicted < 85). All membranous airways with a long-short diameter ratio of 3:1 or less were examined. The smooth muscle and the tissue areas external and internal to the muscle layer were traced using a Bioquant BQ System 4. The same system was used to evaluate the fraction of the submucosa and adventitia taken up by blood vessels. The adventitial, submucosal, and muscle area of the asthmatic airways were greater than those of COPD and control (p < 0.01), and the muscle area was greater in COPD than in control lungs (p < 0.05). These parameters were also greater in the 8 patients with fatal asthma compared with the 7 patients with nonfatal asthma (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Using a computational model, we investigated the effect of the morphologically determined increased airway smooth muscle mass, adventitial mass, and submucosal mass observed in patients with asthma and chronic obstructive pulmonary disease (COPD) on the increase in airway resistance in response to a bronchoconstricting stimulus. The computational model of Wiggs et al. (J. Appl. Physiol. 69: 849-860, 1990) was modified in such a way that smooth muscle shortening was limited by the maximal stress that the muscle could develop at the constricted length. Increased adventitial thickness was found to increase constriction by reducing parenchymal interdependence. Increased submucosal thickness led to greater luminal occlusion for any degree of smooth muscle shortening. Increased muscle thickness allowed greater smooth muscle shortening against the elastic loads provided by parenchymal interdependence and airway wall stiffness. We found that for constant airway mechanics, as reflected by the passive area-pressure curves of the airways, the increased muscle mass is likely to be the most important abnormality responsible for the increased resistance observed in response to bronchoconstricting stimuli in asthma and COPD. For a given maximal muscle stress, greater muscle thickness allows the development of greater tension and thus more constriction of the lumen.

Previous studies have demonstrated that the airway wall in asthma and chronic obstructive pulmonary disease is markedly thickened. It has also been observed that when the smooth muscle constricts the mucosa buckles, forming folds that penetrate into the airway lumen. This folding pattern may influence the amount of luminal obstruction associated with smooth muscle activation. A finite-element analysis of a two-layer composite model for an airway is used to investigate the factors that determine the mucosal folding pattern and how it is altered as a result of changes in the thickness or stiffness of the different layers that comprise the airway wall. Results demonstrate that the most critical physical characteristic is the thickness of the thin inner layer of the model. Thickening of this inner layer likely is represented by the enhanced subepithelial collagen deposition seen in asthma. Other findings show a high shear stress at or near the epithelial layer, which may explain the pronounced epithelial sloughing that occurs in asthma, and steep gradients in pressure that could cause significant shifts of liquid between wall compartments or between the wall and luminal or vascular spaces.

We have examined the effect of airway wall thickening, loss of lung recoil, and airway smooth muscle shortening on the increase in airway resistance using a model of the human tracheobronchial tree. The values for airway wall thickening were determined morphometrically on the postmortem or surgically resected lungs of normal subjects, patients with moderate chronic obstructive pulmonary disease, and patients with severe asthma. Loss of recoil was simulated by deflating airways along their pressure-area curves by 1 to 3 cm H2O. Values of smooth muscle shortening between 20 and 40% were used in the model to generate sigmoidal-shaped "dose-response" curves. The analysis shows that moderate amounts of airway wall thickening, which have little effect on baseline resistance, can profoundly affect the airway narrowing caused by smooth muscle shortening--especially if the wall thickening is localized in peripheral airways. The combination of a loss of recoil and airway wall thickening are more than additive in their effect on simulated airway responsiveness. We conclude that airway wall thickening and a loss of lung recoil can partially explain the airway hyperresponsiveness observed in patients with chronic obstructive lung disease and asthma.

Neutrophils [polymorphonuclear leukocytes (PMNs)] are sequestrated in the lung capillary bed because PMNs are delayed with respect to red blood cells (RBCs) as they pass through these microvessels. The present study examines circulating PMN size in relation to the distribution of capillary segment diameters in human, dog, and rabbit lungs and compares the shape of PMNs in suspension to that found within the pulmonary capillaries. The data show that 61, 67, and 38% of the capillary segments are narrower than the mean diameter of spherical PMNs in the rabbit, dog, and human, respectively. They also show that PMNs deform from a spherical to an ellipsoid shape in the pulmonary capillaries of all three species. These findings are consistent with previous studies showing that the pulmonary circulation restricts the passage of PMNs through the lungs and suggest that PMNs are delayed because they must deform to pass through restrictions encountered in the pulmonary capillary bed. We conclude that the discrepancy between PMN and pulmonary capillary size and the decreased deformability of PMNs with respect to RBCs are major determinants of the delay that PMNs experience with respect to RBCs in the pulmonary circulation.

Morphologic changes in pulmonary muscular arteries may modify the mechanisms that regulate the pulmonary vascular tone and contribute to maintaining an adequate ventilation-perfusion (VA/Q) matching in patients with chronic obstructive pulmonary disease (COPD). To analyze the relationships between the abnormalities of pulmonary muscular arteries and the degree of VA/Q inequality, and to assess the effect of these abnormalities on the changes in VA/Q relationships induced by oxygen breathing, we studied a group of patients with mild COPD undergoing resective lung surgery. According to the degree of airflow obstruction and the increase in VA/Q mismatch produced by 100% O2 breathing (delta logSD Q), patients were divided into three groups: (A) patients with normal lung function, (B) patients with airflow obstruction and a high response to oxygen (delta logSD Q > 0.4), and (C) patients with airflow obstruction and a low response to oxygen (delta logSD Q < 0.4). Pulmonary arteries in Groups B and C showed narrower lumens and thicker walls than in Group A. These morphologic changes were produced mainly by an enlargement of the intimal layer and were more pronounced in Group C than in Group B. The assessment of intimal area as a function of artery diameter showed that the increase in intima in Group C took place predominantly in arteries with small diameters (< 500 microns). The mean intimal area on each subject correlated with both the PaO2 value (r = -0.46, p < 0.05) and the overall index of VA/Q mismatching (r = 0.51, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The obstruction to airflow that develops in some cigarette smokers is thought to be related to inflammation of small airways. However, the mechanism by which inflammation leads to obstruction has not been elucidated. We performed morphometry to determine if the airways of patients with obstruction were thicker than normal. Sixty smokers were selected from those undergoing resectional lung surgery. They were grouped according to their FEV1/FVC ratio (FEV1% control = 77%, FEV1 obstructed = 55%) and matched for age, sex, and height. Wall area (mm2), perimeter (mm), and diameter (mm) were measured by a modification of the technique of James and coworkers (7). The relaxed luminal diameter (mm) and wall thickness (mm) were calculated from these values. A pathology score for inflammation and fibrosis was assigned to each patient, and the percentage of the wall made up of muscle, epithelium, and connective tissue was determined by point counting. Two hundred airways, 90% of which were membranous bronchioles, were measured in each group. The mean-measured luminal diameter in the controls was 0.81 mm and in the obstructed patients 0.70 mm (p less than or equal to 0.05). The regression lines relating wall thickness to calculated luminal diameter showed that the airways of the obstructed patients were thicker throughout the size range measured (p less than or equal to 0.005). The muscle, epithelium, and connective tissue were all increased in the obstructed patients (p less than or equal to 0.001). In addition, the wall thickness correlated with the pathology score (r = 0.6074, p less than or equal to 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)

Neutrophils may play a part in the pathogenesis of the centrilobular emphysema associated with cigarette smoking. The capillary bed of the lungs concentrates neutrophils approximately 100-fold with respect to erythrocytes, producing a large pool of marginated cells. We examined the effect of cigarette smoking on the kinetics of this pool of cells, using 99mTc-labeled erythrocytes to measure regional blood velocity and 111In-labeled neutrophils to measure the removal of neutrophils during the first passage through the pulmonary circulation, their subsequent washout from the lungs, and the effect of local blood velocity on the number of neutrophils retained in each lung region. We observed no difference in these measurements between subjects who had never smoked (n = 6) and smokers who did not smoke during the study (n = 12). However, subjects who did smoke during the study (n = 12) had a significantly slower rate of washout of radiolabeled neutrophils from the lung (0.08 +/- 0.04 of the total per minute, as compared with 0.13 +/- 0.06 in smokers who did not smoke during the experiment and 0.14 +/- 0.08 in non-smokers) (P = 0.02). We also observed an increase in the regional retention of labeled neutrophils with respect to blood velocity in 5 of the 12 subjects who smoked during the study, but in none of the other subjects. We conclude that the presence of cigarette smoke in the lungs of some subjects increases the local concentration of neutrophils, and suggest that the lesions that characterize emphysema may be a result of the destruction of lung tissue by neutrophils that remain within pulmonary microvessels.