The resistance of collateral channels in excised human lungs.

We measured the resistance of collateral channels, R(col), in incomplete interlobar fissures in eight normal and eight emphysematous excised human lungs. Similar measurements were also made from the basal segments to the superior segment of the lower lobe in three normal and five emphysematous lungs. The lobe or segments were inflated through a bronchial cannula; air leaked through collateral channels and out of the other lobe or segment through a pneumotachograph which measured flow. Catheters inserted directly into the lung through the pleural surface on either side of the collateral channels measured the alveolar pressure difference producing collateral flow. R(col) is the ratio of this pressure difference to flow. By also measuring the inflating pressure and the airway pressure at the pneumotachograph, we calculated the lobar or segmental airway resistance, R(aw). In the normal lungs R(col) varied inversely with lung volume and was higher on inflation than on deflation. R(aw) was very small compared to R(col) which ranged from 260 to 3300 cm H(2)O/liter per sec when the distending pressure was 20 cm H(2)O. In the emphysematous lungs on the other hand, R(col) was markedly decreased and ranged from 5 to 20 cm H(2)O/liters per sec at the same distending pressure and was less than R(aw). We conclude that collateral channels are important ventilatory pathways in emphysema. When many units within a lung are ventilated by these pathways there may be disturbances of gas exchange and phase differences between normally and abnormally ventilated areas.

Elastic properties of the centrilobular emphysematous space.

Bronchograms were performed using finely particulate lead on emphysematous lungs obtained at necropsy. X-ray films were taken of these lungs at distending pressures of 0, 5, 10, and 20 cm H(2)O. The volumes of individual centrilobular emphysematous spaces were calculated at each distending pressure from measurements made on these bronchograms and pressure-volume curves were constructed for each space. The pressure-volume characteristics of seven normal lungs and one lung with centrilobular emphysema was also measured. The normal lungs, the lung with centrilobular emphysema, and the centrilobular emphysematous spaces were compared by expressing the volume of air contained in them at each distending pressure as a per cent of the volume contained at 20 cm H(2)O distending pressure. We conclude that centrilobular emphysematous spaces have a high residual volume, are less compliant than normal lung tissue, and are much less compliant than the emphysematous lungs which contain them. Furthermore, these spaces undergo little volume change in the tidal breathing range and probably add a relatively nondistensible series dead space to the surrounding lung parenchyma.

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)

Aspects of chronic airflow obstruction.

This report questions several commonly used definitions and commonly accepted concepts. It suggest that the term, "chronic airflow obstructions," should replace the terms, "chronic obstructive pulmonary disease," "chronic obstructive lung disease," or "chronic airway obstruction," because it is flow that is obstructed. It is suggested the term, "chronic mucous hypersecretion," be used, rather than "chronic bronchitis," and that the latter be avoided. Chronic bronchitis should not be equated with narrowing of the airway and emphysema with loss of elastic recoil. Chronic bronchitis, emphysema, and lesions of the small airways probably occur together more frequently than chance will allow because of a common etiologic agent, tobacco smoke. Chronic mucous hypersecretion without other airway or parenchymal lesions seldom produces airflow obstruction and does not impair prognosis significantly. Central airways are important in chronic airflow obstruction. It is time that someone found out what is happening in subjects with abnormal results on tests of the function of small airways. The definition of "destruction" as it occurs in emphysema is deceptive, and loss of recoil and emphysema may be separate conditions. The dysfunction that occurs in emphysematous lungs is due mainly to associated airway lesions and may perhaps be due in part to the site and nature of emphysematous lesions (as opposed to loss of elastic recoil).

Growth and aging of the normal human lung.

The lung grows primarily by alveolar multiplication, but alveoli also double in size from infancy to adult life. The time at which alveolar multiplication ceases is obscure. As the lung ages it loses alveolar surface area due to alteration in the internal geometry of the lung. Alveolar wall tissue is also lost, thought to reflect loss of capillary bed.

Small airways disease: reproducibility of measurements and correlation with lung function.

Three measurements of small airway dimensions and a measurement of lesions in small airways were made in 32 human lungs obtained at autopsy in order to assess the intraobserver and interobserver variability of these measurements and their interrelationships. The same measurements were then made in 22 lobes resected in patients with known lung function. Small airway dimensions were smaller in surgically resected lobes compared to autopsy lungs suggesting persistence of muscle tone in the surgical specimens.

The lungs and causes of death in the nocturnal oxygen therapy trial.

Autopsy findings and a morphometric study of the lungs were compared in 18 subjects receiving nocturnal oxygen and 15 receiving continuous oxygen in the National Heart, Lung, and Blood Institute Nocturnal Oxygen Therapy Trial (about half of those who died). The emphysema score, average interalveolar wall distance, central airway lesions, peripheral airway lesions, and the ratio of weights of left ventricle plus septum to right ventricle were similar in the two groups. The causes of death in the two groups were also similar. This evidence supports the hypothesis that the improved prognosis observed with continuous oxygen therapy nocturnal oxygen therapy in patients with severe chronic airflow obstruction and hypoxemia was due to treatment. There was a trend for there to be more interstitial fibrosis and type 2 alveolar epithelial cell hyperplasia in those treated with nocturnal oxygen; in the hands of one observer, the type 2 cell hyperplasia was significant.

Lung cytokinetics after exposure to hypobaria and/or hypoxia and undernutrition in growing rats.

Lung cellular dynamics were examined in growing rats from 4 to 7 wk of age after exposure to 1) room air (general controls), 2) hypobaric normoxia, 3) normobaric hypoxia, 4) hypobaric hypoxia, and 5) room air and restricted food intake (weight-matched controls). Tritiated thymidine ([3H]TdR) incorporation diminished in weight-matched controls. In both hypoxic groups, maximum [3H]TdR incorporation occurred on day 3 in all cells of peripheral alveoli, capillary endothelium of central alveoli, airway walls and epithelium, and arterial wall and endothelium, but maximum [3H]TdR labeling of interstitial and unidentifiable cells of central alveoli occurred on day 5. The percent labeling with [3H]TdR was higher in cells of peripheral alveolar walls than in cells of central alveolar walls. Labeling of the interstitium was higher in hypobaric hypoxic than normobaric hypoxic rats. In hypobaric normoxia, DNA synthetic activity increased in alveolar wall cells, except for capillary endothelium. In hypobaric hypoxia, DNA synthesis occurred primarily because of low O2, but low pressure may also affect cytokinetics. [3H]TdR incorporation is greater and earlier in the alveoli of the peripheral part of the lung than central alveoli, and the cellular response of the various cells types is not synchronous.

Lung growth in hypobaric normoxia, normobaric hypoxia, and hypobaric hypoxia in growing rats. I. Biochemistry.

Adaptive changes in cellular and connective tissue components of the lung after chronic exposure to reduced ambient oxygen and/or pressure were studied. Four-week-old male Sprague-Dawley rats were randomly divided into five groups (n = 12 each): 1) general control, room air (GC); 2) hypobaric normoxic; 3) normobaric hypoxic; 4) hypobaric hypoxic; and 5) weight-matched control, restricted food intake (WMC; weight matched to hypobaric hypoxic animals). Lung growth (lung weight and DNA, RNA, protein, hydroxyproline, and desmosine contents) diminished in WMC compared with GC. Somatic growth decreased in hypobaric and normobaric hypoxic rats compared with GC. Lung weight; DNA, RNA, protein, hydroxyproline, and desmosine contents; and RNA/DNA, protein/DNA, and desmosine/DNA ratios increased in both hypobaric and normobaric hypoxic rats compared with WMC. Hydroxyproline and desmosine contents and the hydroxyproline/DNA ratio were significantly higher in hypobaric than normobaric hypoxic rats. Hypobaric normoxia caused a slight somatic growth reduction, but biochemical parameters of lung growth remained unaffected. In conclusion, in growing animals, despite inhibition of lung growth due to reduced food consumption, accelerated lung growth in hypobaric or normobaric hypoxia occurs by hyperplastic and hypertrophic changes. Hypobaric normoxia does not affect lung growth, but connective tissue proteins accumulate slightly more in hypobaric hypoxia than in hypoxia alone.

A comparative study of postpneumonectomy compensatory lung response in growing male and female rats.

Postpneumonectomy compensatory lung response and normal lung growth in the early postnatal period were studied in male and female rats. Four-week-old litter-matched male and female Sprague-Dawley rats were subjected to left pneumonectomy or sham operation and followed for 3 wk. In both sexes after pneumonectomy, lung weight (WL), lung volume (VL), alveolar surface area (Sw), total alveolar number (N(at)), and the amount of DNA and protein increased significantly. In both males and females, WL, VL, and Sw matched those of both lungs of the sham-operated group, but N(at) and the amount of DNA and protein did not. Female pneumonectomy and sham-operated rats were smaller in body weight than males. Absolute WL, VL, Sw, N(at), and the amount of DNA and protein were significantly lower, but specific parameters (per unit body weight) were significantly greater in females than in males. After pneumonectomy, the postcaval lobe increased most in volume (70 and 73% in males and females, respectively). Mean linear intercept and mean chord length of alveoli increased, and the number of alveoli per unit volume decreased more in the postcaval and middle lobes than in upper and lower lobes in both sexes. Postpneumonectomy, loss of elastic lung recoil was observed in females. We conclude that, in certain aspects (WL, VL), compensatory growth matched both lungs of controls, but in others (biochemical, morphometric) it did not. There was evidence of alveolar multiplication, but the dominant effect was enlargement of air spaces.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term consequences of compensatory lung growth.

Left pneumonectomy or left nephrectomy was performed on 10-wk-old littermate male New Zealand White rabbits, and they were killed at 30 wk of age. Thirty-week-old male littermates served as controls. Nephrectomy was done to produce major tissue loss and trauma and to assess blood somatomedin C. At the end of the experiment, the right lungs of the pneumonectomy animals had a greater lung volume, weight, gas-exchanging surface area, and alveolar number than the nephrectomy animals and the controls, and their air spaces were the same size. When compared with both lungs of the nephrectomy group and the controls, lung weight was the same; lung volume, alveolar number, and protein were not significantly less in the pneumonectomy group, but gas-exchanging area (compared with controls only), DNA, and RNA were. After left nephrectomy, the right kidney increased in weight; nephrectomy had no effect on lung size or structure. We conclude that pneumonectomy at age 10 wk in male rabbits results in significant compensatory lung growth, including alveolar multiplication, and this persists to age 30 wk. Compensatory lung growth, however, was incomplete; that is, it did not reconstitute (equal) in all respects that of both lungs of the nephrectomy animals or the controls.

Pulmonary function alterations after 3 wk of exposure to hypobaria and/or hypoxia in growing rats.

We studied lung growth in rats between 4 and 7 wk of age under different conditions. There were five groups, seven animals in each: 1) general controls (ambient pressure and room air, food ad libitum); 2) hypobaric normoxic [barometric pressure (PB) 410 mmHg, PO2 153 Torr]; 3) normobaric hypoxic (ambient pressure, PO2 80 Torr); 4) hypobaric hypoxic (PB 410 mmHg, PO2 80 Torr); and 5) weight-matched controls to hypobaric hypoxic. Residual volume, functional residual capacity, vital capacity, and total lung capacity grew 10-20% more in both hypoxic groups than in weight-matched and general controls. Expiratory flow rates corrected for forced vital capacity decreased, and specific airway resistance increased significantly. In addition, the ratio of forced expiratory volume in 0.1 s to %forced vital capacity, peak expiratory flow rate, and forced maximal midexpiratory flow were also lower in normobaric hypoxic animals compared with weight-matched controls. Above a transpulmonary pressure of 6 cmH2O, flows were reduced in both hypoxic groups. No differences were observed between hypobaric normoxic and general control groups for lung volume and lung function. In weight-matched animals, total lung capacity decreased but lung function remained unchanged. We conclude that accelerated lung growth in hypobaric hypoxia and normobaric hypoxia is dysanaptic. Lung growth in hypobaric hypoxia is primarily induced by low oxygen, but differences between hypobaric hypoxia and normobaric hypoxia suggest a beneficial effect of low pressure.

Pathophysiology of chronic obstructive pulmonary disease.

Chronic airflow obstruction (CAO) is a syndrome that is produced by a variety of lesions which may occur in bronchi (large airways), bronchioles (small airways), and lung parenchyma (gas exchanging lung). These lesions frequently occur together in various combinations because of a common etiologic agent, tobacco smoke. Occasionally, one lesion or another may play a dominant role. The major disease of the large airways is chronic bronchitis, or chronic sputum production, and it is defined clinically. Its morphologic counterpart is mucous gland enlargement. Mucous gland enlargement is poorly related to CAO. Other lesions of the large airways--inflammation, smooth muscle hyperplasia, cartilage atrophy, and bronchial wall thickening--have also been described, but their functional consequences are uncertain. Bronchiolar lesions are well recognized in CAO, but their relative importance may differ in patients with mild CAO, compared to patients with severe CAO. In mild CAO, inflammation is a very important lesion, and its probable consequences--narrowing, fibrosis, and goblet cell metaplasia--have all been found to be important. In severe CAO, inflammation and fibrosis do not appear to be important, but goblet cell metaplasia, bronchiolar tortuosity, and narrowing do. Emphysema is a subset of airspace enlargement. Emphysema is defined anatomically and is the most important component of severe CAO. Several forms of emphysema can be recognized morphologically and may have specific clinical associations. However, in the usual patient with severe CAO, it is the severity, rather than the type, of emphysema, that is most significant. The diagnosis of emphysema depends on a combined approach. Significant factors include the clinical history (age, sex, smoking, chronic bronchitis, dyspnea), radiologic evidence of overinflation, and diminished diffusing capacity for carbon monoxide.

Effects of streptozotocin-induced diabetes on postpneumonectomy lung growth and connective tissue levels.

Diabetes is generally accompanied by abnormal levels of growth hormone and adrenal steroids, hormones known to modulate postpneumonectomy (post-PNX) compensatory lung growth. Thus, we examined the possibility that diabetes may affect post-PNX lung growth processes. Left PNX was performed in young diabetic rats (streptozotocin-induced; 75 mg/kg body weight) (DM-PNX) and in control rats (C-PNX), for comparison with sham-operated control rats (C-SHAM). The rats were permitted free access to food and water. Examination at day 7 after surgery showed that right lung absolute dry weight and absolute DNA, collagen and elastin contents were increased in C-PNX and DM-PNX rats (but only C-PNX values reached those of both lungs in C-SHAM rats). Body weights (BW) of DM-PNX rats were lower than those of C-PNX and C-SHAM rats. Lung DNA/BW in C-PNX and DM-PNX rats were comparable, and matched values for both lungs in C-SHAM rats. Lung dry weight/BW, collagen/BW, and elastin/BW in DM-PNX rats exceeded values in C-PNX rats and even more for values of both lungs in C-SHAM rats. Data of another experiment, comparing DM-PNX rats with body weight-matched (by food limitation) PNX and control rats (WMC-PNX and WMC-SHAM rats, respectively) indicated comparable lung absolute DNA contents in DM-PNX and WMC-PNX rats (which matched values for both lungs in WMC-SHAM rats), however, lung absolute collagen and elastic contents were greater in the DM-PNX rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Lung growth and maturation in experimental oligohydramnios in the rat.

On day 16 of gestation the amniotic sacs of either the right or left uterine horns of timed-pregnant Sprague-Dawley rats were punctured with a 20-gauge needle. The fetuses of the opposite horn served as controls. On day 21 of gestation (1 day prior to natural delivery), the fetuses were delivered by Cesarean section. Amniotic sac puncture resulted in a significant loss of amniotic fluid. Fetal growth retardation occurred. Lung growth was specifically retarded, as indicated by significantly reduced lung weight to body weight ratios and lung volume to body weight ratios following amniotic sac puncture. There appeared to be no effect on the structural units of the lung, since no differences between control and experimental fetal lungs were observed in terms of deoxyribonucleic acid, nonconnective tissue protein, total phospholipid, and disaturated phosphatidylcholine per gm dry lung weight. The ratios of disaturated phosphatidylcholine to total phospholipid and nonconnective tissue protein to deoxyribonucleic acid were unchanged. The volume proportions of saccular air, saccular wall, bronchial and bronchiolar air and nonparenchyma, peripheral airspace size, and surface-to-volume ratio were also unchanged. Thus loss of amniotic fluid significantly affected lung growth, more than it affected overall body growth, without having an effect on lung maturation.

Role of calmodulin as an endogenous initiatory factor in compensatory lung growth after pneumonectomy.

Compensatory lung growth after pneumonectomy is a well established phenomenon in young humans and experimental animals. To date, the cellular initiating and/or regulatory factor(s) responsible for this growth response have yet to be established. We have studied changes in lung content and activity of calmodulin, a calcium-dependent regulatory protein in relation with lung mass and DNA content during postpneumonectomy compensatory lung growth in 4-week-old rats. We observed that after left pneumonectomy, right lung calmodulin content (measured by radioimmunoassay) and calmodulin activity (measured by cyclic nucleotide phosphodiesterase activation) were increased at days 1 and 2 after surgery in the pneumonectomized rats, preceding the increase of lung mass and DNA content which started at day 3. Treatment of the pneumonectomized rats with a highly specific calmodulin antagonist, trifluoperazine, immediately after the surgery, resulted in diminished lung calmodulin activity, sparing the calmodulin content, and in concomitant reduction of lung mass and DNA content to values intermediate between those of controls and the pneumonectomized animals. Based on these findings, we conclude that calmodulin may be an important intracellular (possibly, autocrine) initiatory or facilitatory factor in compensatory hyperplastic lung growth after pneumonectomy.

The effect of age on postpneumonectomy growth in rabbits.

To assess the effect which age at pneumonectomy has on pulmonary compensatory growth, male New Zealand white rabbits underwent left pneumonectomy or sham thoracotomy at 10, 18, or 26 weeks of age. Morphometric and biochemical evaluation of the remaining lungs was carried out four weeks later. There was significant compensatory growth in terms of lung volume, weight, DNA, RNA, and protein in all three age groups. Lung volume response was incomplete, i.e., right lung volume of the experimental animals did not match the volume of both lungs of controls; other variables were not significantly different between the right lung of experimentals and both lungs of the controls. An unchanged surface area per unit volume accompanied by a stable mean linear intercept indicated that alveolar multiplication occurred in the 10 and 18 week age groups. The oldest group had significantly decreased surface area per unit volume and significantly increased mean linear intercept, suggesting an increase in the size of existing alveoli at 26 weeks of age.

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 1 1/2 postnatal years. The lungs of BPD and HMD infants had higher contents of DNA, alkalisoluble 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 I/III 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.

The in vitro effect of triamcinolone acetonide on branching morphogenesis in the fetal rat lung.

We have studied the effect of triamcinolone acetonide (TAC) on airway morphogenesis of the Sprague-Dawley fetal rat in whole organ lung cultures from day 15 to day 21 of equivalent gestational age (6 days in culture). TAC produced an increased number of peripheral buds from day 18 onward and the airway and airspaces had larger lumens. Airway branching was increased compared to controls, and there was a higher proportion of airway epithelium and a lower proportion of mesenchyme. Cell height was significantly lower in TAC treated lungs except on day 17. This was due to accumulation of glycogen prior to the increased branching activity. In both controls and TAC-treated lungs, peripheral bud number and volume proportion of epithelium increased with time in culture, whereas volume proportion of mesenchyme, mean chord length of airways and airspaces, and epithelial cell height decreased. These changes were more pronounced in the TAC-treated group and were significant. However, TAC-treated lungs were morphologically irregular. We conclude that TAC has a direct effect on airway morphogenesis and it promotes growth of morphologically abnormal lungs. TAC also appears to enhance airway branching and morphologic changes interpreted as increased epithelial maturation.

Diminished radial count is found only postnatally in Down's syndrome.

Acinar complexity was assessed using the radial count in 23 patients with Down's syndrome. Late intrauterine growth of the lung is not impaired, and acinar complexity is normal. Thereafter, decreased acinar complexity occurs and is grossly and microscopically apparent by 4 months of age. The gross appearance is characteristic, consisting of a diffuse and uniform porosity of the cut surface of the lung. Microscopically, this appearance is due to the presence of dilated alveoli and alveolar ducts. Children and adults with Down's syndrome have a significantly reduced number of alveoli, which are enlarged. In the majority of cases, the alveoli have a double capillary network that has not been described in any other lung condition. No correlation could be established between the radial count and the presence or absence of double capillary network, hypertensive pulmonary vascular disease, or congenital heart disease. The unique appearance of the lung in Down's syndrome results from failure of the lung to develop properly in the postnatal period, presumably genetically determined.