William M. Thurlbeck

Postnatal human lung growth.

Standard morphometric methods were applied to the lungs of 36 boys and 20 girls aged from 6 weeks to 14 years, dying as a result of trauma or after short illnesses. Individual lung units, alveolar dimensions, and number of alveoli per unit area and volume did not differ between boys and girls, but boys had bigger lungs than girls for the same stature. This resulted in a larger total number of alveoli and a larger aveolar surface area in boys than in girls for a given age and stature. There may be more respiratory bronchioles in boys than girls. There was rapid alveolar multiplication during the first two years of life and alveolar dimensions and number of alveoli per unit area and volume did not change much during this period. There was little or no increase in the total number of alveoli after the age of 2 years but the data are hard to interpret. There is a wide scatter of the total number of alveoli in the growing lung, in keeping with the observation that the total number of alveoli is very variable in adults. Prediction data are given for the various morphometric variables studied.

Pulmonary Hypoplasia in Down's Syndrome

We studied the lungs of seven patients of various ages who had Downs syndrome, to determine whether they had abnormalities in pulmonary development. Six of the seven had hypoplastic lungs. Five had congenital heart disease, but pulmonary hypoplasia was of equal severity, irrespective of the presence or absence or the type of congenital heart disease. Three other patients with congenital heart disease but without Downs syndrome had lungs that were equally diminished in volume. However, these lungs lacked the structural abnormalities seen in Downs syndrome, which consisted of a diminished number of alveoli in relation to acini and enlarged alveoli and alveolar ducts. The patients with Downs syndrome also had a smaller total number of alveoli and a smaller alveolar surface area. We speculate that the smaller alveolar surface area is accompanied by loss of capillary surface area, which is responsible for the aggravation of pulmonary hypertension in Downs syndrome.

Pathology of Chronic Airflow Obstruction

Classification of chronic airflow obstruction may be based on the site of the obstructing lesions. It is seldom that only one type of lesion is present, but one may often dominate. In chronic bronchitis, the major disease of large airways, chronic mucus hypersecretion, is reflected by an increase in size of bronchial mucous glands. This may be a factor in airway narrowing, especially with coexisting edema of the airway wall. Excess intralumenal mucus compounds the obstruction. Increased airways reactivity is present in 15 to 70 percent of patients with chronic airflow obstruction. Increased airway muscle and cartilage atrophy are features of chronic bronchitis, but the association of increased muscle with increased airway reactivity is poor. Inflammation of the small airways (bronchiolitis) is a significant complication for cigarette smokers and is an important cause of mild chronic airflow obstruction. Goblet cell metaplasia is a reflection of chronic small airways inflammation and, together with intralumenal mucus, is an important feature. Permanent narrowing of the small airways presumably results from inflammation with consequent fibrosis, while functional narrowing results from release of mediators of inflammation. Increased muscle mass is present in some cases. Distortion and irregularity of small airways related to emphysema are major factors in severe obstruction. Lesser degrees of emphysema may be associated with a diminished number of alveolar attachments and mild chronic airflow obstruction. Emphysema, the dominant lesion in patients with severe chronic airflow obstruction, results from parenchymal lesions. Centrilobular emphysema, in which the respiratory bronchioles are selectively or dominantly involved, is the most common form.(ABSTRACT TRUNCATED AT 250 WORDS)

Postnatal lung growth after repair of diaphragmatic hernia.

The lungs of two patients who died eight months and 64 months after repair of a left-sided diaphragmatic hernia on the first day of life were examined. Lung volumes were appropriate for the size of the children, and the ratio of right lung volume to left lung volume was also normal in both patients. The lungs, however, were grossly abnormal with evidence of enlargement and destruction of respiratory tissue. The left lung was affected more than the right in both subjects. In one patient the total number of alveoli in the lungs was similar to that of normal children of the same age, but this was because the right lung had more than twice as many alveoli as the left lung. It appears that alveolar multiplication is impaired after repair of diaphragmatic hernia. The number of bronchioles was reduced in the infant with very few alveoli, and there may have been too few bronchioles in the other patient.

Biochemical, clinical, and morphologic studies on lungs of infants with bronchopulmonary dysplasia

We correlated clinical, biochemical, and morphologic findings in the lungs of 48 infants dying of either bronchopulmonary dysplasia (BPD) or hyaline membrane disease (HMD) to obtain a better idea of the disease process. The infants ranged from 24 weeks of gestation to 1½ postnatal years. The lungs of BPD and HMD infants had higher contents of DNA, alkali‐soluble protein, hydroxyproline, and desmosine, as well as increased concentrations of DNA, hydroxyproline, and desmosine when compared with the lungs of 72 control infants. BPD was classified histologically into 4 groups: Group I was a phase of acute lung injury; Group II the proliferative phase; Group III the phase of early repair; and Group IV the phase of late repair. We saw a significant increase in hydroxyproline concentration in Groups II and III. The ratio of type VIII collagen decreased in BPD Groups II to IV. Desmosine was significantly higher only in Group III than in controls. When the pathological classification was related to biochemical and clinical features of BPD, the classification showed dependence on the number of days the infant survived postnatally and not on the gestational age of the infant. The number of days on assisted ventilation was a slightly better predictor of the disease classification than days on > 60% oxygen. A statistical model correctly predicted the pathologic classification 83% of the time. Pediatr Pulmonol. 1996; 22:215–229.

The national institutes of health intermittent positive pressure breathing trial-pathology studies. III. The diagnosis of emphysema

In an attempt to predict the severity of emphysema in patients with moderately severe and severe chronic air-flow obstruction, antemortem pulmonary function data, including spirometry, subdivisions of lung volumes, diffusing capacity (transfer factor) for carbon monoxide, and elastic recoil were assessed in 46 patients who were autopsied during the National Institutes of Health Intermittent Positive Pressure Breathing Clinical Trial and we compared these to the morphologic severity of emphysema. The severity of emphysema was graded by the panel grading method using whole lung, paper-mounted (Gough-Wentworth) sections and the mean linear intercept (Lm). The FEV1 and FEF25-75 of the FVC, the DLCO, the diffusing capacity for carbon monoxide, and subdivisions of lung volumes showed significant but low order correlations with the emphysema score and Lm. Total lung capacity, determined by plethysmography, was better related to emphysema in this study than in others in which TLC was measured by helium dilution. Volume-pressure data fitted to the exponential equation (V = A - Be-KP) yielded a low order, but a significant relationship between Lm and the exponential constant (K), but not between K and the panel emphysema score. We conclude that the recognition of the presence and severity of emphysema continues to require a multivariate approach including clinical history, assessment of air-flow obstruction via routine spirometry, radiologic assessment of the lung with emphasis on total lung capacity, and evaluation of the diffusing capacity for carbon monoxide.

Post-mortem lung volumes.

The volumes of 78 adult human lungs at necropsy after fixation with intrabronchial 10% formaldehyde at a transpulmonary pressure of 25 cm of water (VL) were similar to their total lung capacity (TLC) as assessed radiologically (VX). Corrected for stature, VL and VX did not increase with age in non-emphsematous lungs, nor did the radio of VL to VX (VL/VX) change with age. VL and VX relative to body length increased with emphysema, and the increase even occurred in lungs from men with trivial or equivocal amounts of emphysema. Thus alteration of the mechanical properties of the lung may precede the appearance of obvious emphysema. VL/VX was not affected by the presence or severity of emphysema. The right lung formed 53% of VL with a range of 49-58% in apparently normal lungs. The amount of air in 13 human lungs at necropsy averaged 61% of TLC with a wide variation, indicating that this is not a useful point at which to measure lung dimensions. It is concluded that the volume of lungs fixed with formaldehyde at a transpulmonary pressure of 25 cmH2O closely approximates to total lung capacity.

Effect of Hypoxia and Hyperoxia on Postpneumonectomy Compensatory Lung Growth

To study the effect of chronic hyperoxia and hypoxia on pneumonectomy-induced compensatory lung growth, 4-week-old male rats were randomly divided into 4 groups: pneumonectomy controls, pneumonectomy hyperoxic group (fraction of ambient oxygen [FO2] 0.35), pneumonectomy hypoxic group (FO2 0.14), and unoperated controls. After 2 weeks, somatic growth of pneumonectomy hypoxic rats was diminished. Compared to unoperated controls, lung weight increased in all pneumonectomy groups but lung volume increased only in pneumonectomy control and pneumonectomy hypoxic rats. Alveolar surface area also increased in pneumonectomy control and pneumonectomy hypoxic animals. Lung weight, volume, and alveolar surface area in pneumonectomy hypoxic rats were also significantly higher than in pneumonectomy hyperoxic rats. When lung weight, volume, alveolar surface area, and total number of alveoli were normalized for body weight, the values were significantly higher in pneumonectomized hypoxic rats than in the pneumonectomy control and pneumonectomy hyperoxic groups. Maximal increase in volume occurred in the post-caval and upper lobes in all pneumonectomized groups. Compared to unoperated rats, mean linear intercept also increased in the post-caval lobe in all pneumonectomized groups. The results suggest that 2 weeks after left pneumonectomy, compensatory lung response is incomplete. Chronic hypoxia enhances, whereas hyperoxia inhibits compensatory lung growth. The post-caval and upper lobes respond more and the lower lobe responds less following left pneumonectomy in both hypoxia and hyperoxia.

Time course of lung growth following exposure to hypobaria and/or hypoxia in rats.

Four-week-old rats were divided into five groups: general controls, weight-matched controls (weight matched to hypobaric hypoxia), hypobaric hypoxia, normobaric hypoxia, and hypobaric normoxia. Lung growth impairment in weight-matched animals occurred by reduction in cell number and size. In both hypoxic groups, lung weight, RNA and protein were significantly higher on day 3, and DNA on day 5 and remained higher thereafter. Maximum 3H-TdR incorporation occurred on day 3 in both hypoxic groups. Hypoxia increased RNA/DNA ratio on day 1 and protein/DNA on day 3. Following 3 days of recovery, DNA synthesis and RNA/DNA ratio of hypoxic groups and controls were identical. DNA synthesis also doubled on day 5 in hypobaric normoxia compared to general controls. Hypoxia up regulates lung growth despite down regulation by undernutrition. Maximum lung growth stimulation occurs during early exposure by cellular hypertrophy followed by hyperplasia. Low pressure by itself also stimulates lung growth. Cellular activity returns immediately to normal levels after removal of hypoxic stimulus.

Oncocytes in human bronchial mucous glands

Oncocytes were found in the bronchial glands of 30 of 33 lungs in which the left bronchial tree was examined. They were found with similar frequency in the main, upper and lower lobe bronchi. They were found more commonly with increasing age and were most frequent in the collecting duct of the bronchial glands. However, they were absent from the collecting duct in 14 cases. They were not increased in chronic bronchitics. It is unlikely that bronchial oncocytes have a specific function in bronchial gland ducts but they may represent a curious form of degeneration of epithelial cells as do oncocytes in other organs.