Cellularity of the alveolar walls in smokers and its relation to alveolar destruction. Functional implications

Inflammatory cells are believed to play an important role in the pathogenesis of emphysema; however, a relationship between presence of cells in the lung parenchyma and its destruction has never been shown. The aim of this study was to quantitate alveolar septal cellularity in smokers' lungs and to investigate its relationship with parenchymal destruction and lung function. The lungs of 23 smokers (SS) undergoing thoracotomy for localized pulmonary lesions were compared with those of eight nonsmokers (NS) and five smokers (AS) who died suddenly of nonrespiratory causes. Pulmonary function tests were performed within 1 wk of surgery in SS. For each subject, we quantitated alveolar wall cells (CELLS), an index of alveolar wall destruction (DI), and the mean linear intercept (Lm). As no significant differences were found between S and AS with regard to these indices, we combined them (Group S) for comparison with NS. Although Lm was not significantly different between S and NS, (0.331 +/- 0.072 versus 0.288 +/- 0.038), CELLS and DI were higher in S than in NS (48 +/- 8 versus 25 +/- 2 cells/mm, p less than 0.001; 47 +/- 20 versus 17 +/- 5, p less than 0.001, respectively). Further, CELLS and DI were significantly correlated (r = 0.799, p less than 0.001). The number of polymorphonuclear cells (PMN) in S can exceed that in NS by as much as 5-fold; however, PMN were inversely correlated with parenchymal destruction (DI) (r = 0.598, p less than 0.01). Thus, smokers' lungs have alveolar septal hypercellularity, possibly inflammatory, and closely related to destruction involving cells other than the PMN.     

Behavior of morphometric indices in pancreatic elastase-induced emphysema in rats

Two morphometric indices, the destructive index (DI), a measure of alveolar wall destruction, and the proportion of destroyed alveolar attachments to the airways (AA), have been proposed as measures of early lung destruction in human smokers. The aim of this study was to compare DI and AA to the usual measure of airspace enlargement—the mean linear intercept (Lm)—in experimental emphysema. Porcine pancreatic elastase was administered intratracheally to 2 groups of Brown Norway rats (high-dose, n=8, 1 IU/g body weight; low-dose, n=4, 0.7 IU/g; control, n=7). Total lung capacity (TLC), functional residual capacity (FRC) and pressure-volume curves were measured 3 weeks after administration of elastase. Lung elasticity was assessed by chord compliance (Cst). Administration of high-dose, but not low-dose, elastase led to significant increases in FRC and TLC. Cst significantly increased after high-dose elastase compared to controls (p < 0.01). Lm increased after both low-dose and high-dose elastase compared to controls (p<0.01); DI and AA were increased only after high-dose elastase. Significant correlations were found between each morphometric index and Cst; the highest correlation was with AA. Behavior of the morphometric indices in this model differed from that reported in human smokers: Lm was a more sensitive measure of destruction than DI, reflecting a process marked by predominance of airspace enlargement over alveolar septal breaks. These differences from human smokers may result from a differing underlying pathogenesis of lung destruction.     

Destructive index: a measurement of lung parenchymal destruction in smokers

Destruction of alveolar walls is considered by most observers to be the most important part in the definition of emphysema, yet it has never been precisely defined and quantitated. We therefore attempted to devise a reliable microscopic technique to quantitate alveolar destruction that would be both sensitive to disease and easy to perform. Using a point-count system, we obtained an index of parenchymal destruction that represents the percentage of destroyed space as a fraction of the total alveolar and duct space. We have called this measurement the destructive index (DI). In the lungs of 8 nonsmokers and 23 smokers, we quantitated the DI and compared it with the mean linear intercept (Lm) and with pulmonary function in smokers. Although Lm was not significantly different in the 2 groups, significant differences between the DI of smokers and nonsmokers (p less than 0.005) were found. In addition, the DI correlated with FEV1(-0.43, p less than 0.05), MMEF (r = -0.44, p less than 0.05), and recoil pressure at 90% TLC (r = -0.61, p less than 0.05) in smokers. These findings suggest that the destructive component of emphysema can be easily quantitated microscopically, occurs in smokers before dimensional changes are evident (i.e., increased Lm), and influences lung function. Therefore, the quantitation of this destruction (DI) could add greatly to the microscopic definition of emphysema, complementing the information given by the dimensional component of emphysema (Lm).     

The "destructive index" in nonemphysematous and emphysematous lungs. Morphologic observations and correlation with function

We examined the relationship of the newly described "Destructive Index" (DI) to emphysema using nine nonemphysematous and 13 emphysematous lungs obtained at autopsy. The amount of emphysema was assessed by the panel method (emphysema grade, EG) and measurement of the mean linear intercept (Lm). The DI depends on three components--alveolar wall/duct disruption, DId; alveolar fibrosis, DIf; and classic emphysema, DIe. DIf was a minor component in our series. The mean DI was 5.8 +/- 2.5, 10.9 +/- 3.9, and 55.7 +/- 7.0% (+/- 1 SEM) in the nonemphysematous (panel grade EG = 0), mild (0 less than EG less than or equal to 25), and moderate to severe (30 less than or equal to EG less than or equal to 60) emphysematous lungs, respectively. The increase in the DI in mild emphysema did not reach significant levels (p less than 0.2). The mean DId was 5.6 +/- 2.5, 10.0 +/- 4.0, and 12.8 +/- 3.9% in the above categories, and the DId in mild emphysema did not differ significantly from that of the nonemphysematous lungs. Lm showed a similar trend and alveolar disruption did not precede airspace enlargement, rather both changes appeared to advance in parallel. The DI correlated closely with EG (r = 0.83, p less than 0.01), but this was due to the component of DIe. The DIe increased steeply in the lungs with EG greater than or equal to 30.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lack of type II cells and emphysema in human lungs

Ten surgically removed human lungs or lobes were studied, to assess the relationship between the abundance of type II alveolar epithelial cells and the degree of emphysema. Type II cell abundance (total number as well as percentage of the total parenchymal cell population) was determined in sections of randomly selected tissue samples of these lungs or lobes by using a type II cell specific antibody specific anti-lavage serum (SALS-Hu), which recognizes surfactant-associated proteins. In these tissue samples we also determined the degree of emphysema with the aid of a number of morphometric parameters, destructive index (DI), mean linear intercept (Lm in mm), and the number of normal alveolar attachments on (pre)terminal bronchioles (normal AA.mm.1). We subsequently calculated the Spearman rank correlation coefficients (rs) between the abundance of type II cells and parameters for emphysema. We found a significant negative correlation between the percentage of type II cells and DI at tissue sample level (rs = 0.55; p = 0.02). We also calculated correlation coefficients between the abundance of type II cells and the degree of small airways disease in (pre)terminal and respiratory bronchioles (SADscore), lung function, age and smoking habits. The results suggest a role for type II cells in the pathogenesis of emphysema.     

Cellular and connective tissue changes in alveolar septal walls in emphysema

Emphysema is commonly defined as enlargement of airspaces distal to terminal bronchioles accompanied by destruction of alveolar walls, but without obvious fibrosis. Morphometric techniques were used to correlate changes in components of the alveolar septa surrounding enlarged airspaces in human emphysema with the mean linear intercept (Lm) of those airspaces. Alveolar and capillary surface density decreased with increased Lm, but the ratio of these surface densities to each other remained close to normal for mild to moderate increases in Lm. This suggests that the decreased gas exchange observed in emphysema is initiated by a total loss of septa and not by selective pathological changes of the microvasculature. Increases in septal wall thickness directly correlated with increases in Lm. For the mild to moderate emphysema lesions included in this study, an increase of 100% in Lm correlated with a 130% increase in the relative volume of the alveolar septal interstitium. Significant increases occurred in both elastin (0.14 to 0.56 microm(3)/microm(2) basement membrane [BM]) and collagen (0.49 to 1. 63 microm(3)/microm(2) BM). The increase in elastin and collagen raises the possibility of a remodeling process in the connective matrix in alveolar walls. Whether or not the new connective tissue represents a disordered, nonfunctional regional response needs to be determined.     

Oral N-acetylcysteine attenuates pulmonary emphysema and alveolar septal cell apoptosis in smoking-induced COPD in rats

Background and objective:   The role of apoptosis in lung destruction in emphysema/COPD is increasingly being recognized. The relationship between anti-oxidants and alveolar septal cell apoptosis in COPD lungs remains to be elucidated. The aim of this study was to investigate the effects of the anti-oxidant, N -acetylcysteine (NAC), on the development of emphysema and alveolar septal cell apoptosis in smoking-induced COPD in rats.
Methods:   Sprague–Dawley rats ( n  = 48) were randomly assigned to normal, COPD, sham and NAC groups. The effects of treatment were assessed by measuring the levels of vascular endothelial growth factor (VEGF) in BAL fluid by ELISA, VEGF and VEGF receptor-2 (VEGFR2) protein expression by western blotting, and the apoptotic index (AI) of alveolar septal cells by terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) assay. Histopathological evaluations (mean linear intercept (MLI), destructive index (DI)) and lung function measurements were performed.
Results:   FEV_0.3/FVC and PEF were lower in the COPD group than in the normal group. MLI and DI were lower in the NAC-treated group than in the COPD or sham-treated groups. As confirmed by western blotting, the levels of VEGF in BAL fluid were higher in the NAC-treated group than in the COPD group. VEGFR2 protein expression was higher in the NAC-treated group than in the COPD group. The AI was significantly lower in the NAC-treated group than in the COPD group. There was an inverse correlation between levels of VEGF in BAL fluid and the AI of alveolar septal cells.
Conclusions:   NAC attenuates lung damage, pulmonary emphysema and alveolar septal cell apoptosis by partly reversing the decrease in VEGF secretion and VEGFR2 protein expression in smoking-induced COPD in rats.     

Alveolar fenestrae in smokers. Relationship with light microscopic and functional abnormalities

We studied 12 smokers' lungs with scanning electron microscopy in order to analyze the distribution and size of alveolar fenestrae and their relationship to the average distance between alveolar walls (Lm) and lung function. Alveolar fenestrae in areas near terminal airways (respiratory bronchioles and alveolar ducts) were consistently larger than fenestrae far from airways (alveoli). Fenestrae in near areas increased in size as Lm increased (r = 0.845, p less than 0.001), whereas no correlation between Lm and fenestrae size in far areas was found (r = 0.281, NS). The overall area of fenestrae (near and far) correlated significantly with FEV1 (r = -0.745, p less than 0.01), MMEF (r = -0.752, p less than 0.01), and PL90 (r = -0.804, p less than 0.05). However, when subdivided into near and far, only fenestrae near the small airways showed a significant correlation with function. These findings suggest that in smokers with mild to moderate emphysema, destruction affects preferentially the areas around the terminal airways (near areas), and these changes, although small, might play an important role in the lung function.     

Cigarette smoking causes accumulation of polymorphonuclear leukocytes in alveolar septum

The polymorphonuclear leukocyte (PMN) may play an important role in the pathogenesis of emphysema. Cigarette smoking is associated with the accumulation of PMN in the lung as determined by bronchoalveolar lavage. We enumerated alveolar wall PMN on histologic sections from lungs of humans and hamsters with and without cigarette smoke exposure. In human nonsmokers, there were 0.9 +/- 0.2 PMN/mm alveolar wall. In cigarette smokers without emphysema, there were 2.1 +/- 0.3 PMN/mm alveolar wall (p less than 0.01), and in cigarette smokers with emphysema, there were 2.4 +/- 0.7 PMN/alveolar wall (p less than 0.05). There were 1.7 +/- 0.3 PMN/mm alveolar wall in the lungs of hamsters unexposed to cigarette smoke compared with 3.1 +/- 0.3 PMN/mm alveolar wall in smoke-exposed hamsters (p less than 0.005). Although cigarette smoking causes PMN to accumulate within alveolar septa, the accumulation does not seem to be closely related to the development of emphysema. This suggests that additional or other factors are important in the pathogenesis of emphysema.     

Lymphocyte population and apoptosis in the lungs of smokers and their relation to emphysema.

Previously, it had been shown that T-lymphocytes are the predominant inflammatory cells found in the alveolar wall of smokers and their numbers correlated with the extent of emphysema. However, the phenotype of these cells was not defined. The aim of this study was to describe the different T-cell phenotypes and investigate the possible presence of apoptosis in the lung parenchyma of smokers. Samples from lungs were obtained at surgery from 15 patients who smoked and six who had never smoked. Samples were frozen and prepared for histological and immunocytochemical examination. Slides were stained for CD3+, CD4+, CD8+, gammadelta T-cells, CD56 natural killers ((NK) cells), and elastase (neutrophils). Anti-CD95 monoclonal antibodies and in situ end-labelling techniques were used to detect Fas expression and apoptosis. Positive staining cells were expressed as cells-mm alveolar wall-, percentage of total cells, and Fas/APO and apoptosis index. Emphysema was identified macroscopically, microscopically and reported as present or absent. All subjects had pulmonary function tests before surgery. Neutrophils were the predominant cell in the lung parenchyma of nonsmokers and smokers without emphysema. In smokers with emphysema, the CD3+ and CD8+ were the predominant cells (p<0.05) in the alveolar wall. gammadelta cells were increased in all smokers and no increased numbers of NK cells was found. The T-cell numbers x mm alveolar wall(-1) showed a bilinear relationship with the amount smoked increasing at an inflection point of 30 packs yr(-1) (R2= 0.345; p < 0.01). Apoptosis in smokers showed a bilinear relationship with the amount smoked increasing sharply in smokers with emphysema (R2=0.3613; p < 0.009). It is concluded that the pathogenesis of emphysema might be mediated by T-lymphocytes, mainly CD8+ cytolytic T-cells, and that apoptosis might be one of the mechanisms of lung destruction leading to the development of emphysema. If this is the case, it could be speculated that T-cell inflammation is a response to antigenic stimuli originating in the lung and induced by cigarette smoking.     

Membranous and respiratory bronchiole disease in patients with normal air-flow and mild air-flow limitation

In order to evaluate the role of membranous (MB) and respiratory bronchioles (RB) in patients with normal and mild airflow limitation, we quantitatively assessed the pathological change of MB, RB and alveoli in the pathological specimens of 42 patients who required surgery for removal of a solitary pulmonary nodule. We also measured the destructive index (DI), to evaluate the destruction of alveolar walls. High resolution CT scan and pulmonary function tests were performed within 1 month of resection. Results of the pulmonary function tests correlated with pathological changes of RB better than with MB. Significant correlation between the emphysema score of resected lung and the pathological change of MB and RB was observed. There was also significant correlations between the CT score or DI and RB changes. However, there was no significant correlation between the CT score or DI and the change of MB. There were significant differences between smokers and nonsmokers in the results of pulmonary function test, pathological changes of RB and severity of emphysema. We postulate that RB is responsible for subtle functional abnormalities in the early stages of chronic obstructive pulmonary disease.     

The senile lung. Comparison with normal and emphysematous lungs. 2. Functional aspects.

Senile lungs are characterized by a homogeneous enlargement of the alveolar airspaces, without fibrosis or destruction of their walls. Study of the functional characteristics of excisea senile lungs showed an increase in minimal air and a shift to the left of the elastic recoil pressure-volume curves, less pronounced than in emphysematous lungs. Maximal expiratory volumes and flows were normal. Total lung capacity was not significantly increased, but this may be a consequence of preagonal edema. Comparison of normal, senile, and emphysematous lungs showed a close relationship between recoil pressures and mean linear intercept, Lm, and between forced expiratory volume in 1 s and diameter and density of the membranous bronchioles. It is concluded that airspace enlargement may precede emphysema and may be responsible for changes in lung elasticity. In this respect, senile lungs are an example of the functional changes caused by an isolated airspace enlargement.     

Cigarette smoking and lung destruction. Accumulation of neutrophils in the lungs of cigarette smokers

It has been hypothesized that lung destruction in persons with emphysema associated with cigarette smoking is mediated by elastase released by neutrophils that have migrated to the alveolar structures in response to cigarette smoke. To directly evaluate this hypothesis, cell suspensions, isolated from bronchoalveolar lavage fluid and from open lung biopsies of nonsmokers and cigarette smokers with normal lung parenchyma and from open lung biopsies of nonsmokers and cigarette smokers who have sarcoidosis were evaluated for the presence of neutrophils. A significantly increased number of neutrophils was present in the cell suspensions isolated from bronchoalveolar lavage fluid and from open lung biopsies of both normal and sarcoid cigarette smokers compared with that in the nonsmokers (p less than 0.01, each comparison). Evaluation of the alveolar macrophages present in lavage fluid suggested a mechanism by which neutrophils may be attracted to the lungs of cigarette smokers: alveolar macrophages of cigarette smokers release a chemotactic factor for neutrophils, whereas alveolar macrophages of nonsmokers do not. In addition, alveolar macrophages of nonsmokers, after exposure to cigarette smoke, in vitro, are stimulated to release this chemotactic factor. These studies demonstrate that an increased number of neutrophils are present in the lungs of cigarette smokers compared with that in nonsmokers and suggest that cigarette smoke may attract neutrophils to the lung by stimulating alveolar macrophages to release a potent chemotactic factor for neutrophils.     

The CT diagnosis of emphysema and correlation with pathologic findings

It is difficult to diagnose clinically silent or mild emphysema. The efficacy of CT scans for the diagnosis of emphysema has attracted attention and comparisons have been made between CT images and the pathological grade of emphysema in resected lungs. With a view to determine to what extent high resolution CT images are accurate concerning the diagnosis of mild emphysema, we conducted an extensive comparative study on CT scores of emphysema, based on high resolution CT, the pathology score derived from the cut surface of the lung identical in its plane with that of the CT and destructive index (DI) which is said to be instrumental in representing the degree of deterioration of alveolar walls in the same regions of the lungs. In this study, 42 patients who underwent thoracotomy and their lung specimens including a solitary nodule of considerable size have been employed. The CT scores and pathology scores depend on the picture grading system developed by Thurlbeck and coworkers for the basis of counting. The findings were such that with 1 mm collimation, the CT scores ranged between 12 and 57 with a mean +/- SD of 22.1 +/- 9.6 (n = 35) while with 5 mm collimation, the CT scores ranged between 7 and 46 with a mean +/- SD of 16.5 +/- 8.3 (n = 33). The pathology scores stood at 10 to 57 with a mean +/- SD of 23.2 +/- 9.8 (n = 42).(ABSTRACT TRUNCATED AT 250 WORDS)     

An animal model of autoimmune emphysema

Although cigarette smoking is implicated in the pathogenesis of emphysema, the precise mechanisms of chronic progressive alveolar septal destruction are not well understood. We show, in a novel animal model, that immunocompetent, but not athymic, nude rats injected intraperitoneally with xenogeneic endothelial cells (ECs) produce antibodies against ECs and develop emphysema. Immunization with ECs also leads to alveolar septal cell apoptosis and activation of matrix metalloproteases MMP-9 and MMP-2. Anti-EC antibodies cause EC apoptosis in vitro and emphysema in passively immunized mice. Moreover, immunization also causes accumulation of CD4+ T cells in the lung. Adoptive transfer of pathogenic, spleen-derived CD4+ cells into naive immunocompetent animal also results in emphysema. This study shows for the first time that humoral- and CD4+ cell-dependent mechanisms are sufficient to trigger the development of emphysema, suggesting that alveolar septal cell destruction might result from immune mechanisms.     

Exponential analysis of the pressure-volume curve. Correlation with mean linear intercept and emphysema in human lungs

We investigated the effect of obvious emphysematous lesions and the mean airspace size in the lung surrounding these lesions on the exponential constant K of the lung pressure-volume curve. The severity of the centrilobular emphysematous (CLE) lesions was determined in resected lung specimens, and the mean linear intercept (Lm) was measured on random histologic sections taken from regions without obvious emphysema. The exponential constant K was determined by fitting lung pressure-volume data obtained from the patient just prior to resection to the equation V = A - Be-KP. This allowed us to compare patients with little or no emphysema that had either normal (0.16 +/- 0.03 SD; n = 12) or increased (0.27 +/- 0.04 SD; n = 12) K to other patients that had severe emphysema but either normal (0.17 +/- 0.01 SD; n = 10) or increased (0.25 +/- 0.03 SD; n = 10) K. In subjects without emphysema, K was significantly related to Lm, suggesting that K is a measure of mean alveolar size. In the subjects with emphysema, a lower value for K was associated with more severe airway dysfunction and gas trapping. We conclude that K reflects airspace size except when airway closure subtracts the contribution of lung units from the deflation pressure-volume curve.     

Increased levels of cell death and proliferation in alveolar wall cells in patients with pulmonary emphysema

BACKGROUND: Pulmonary emphysema, a major component of COPD, is pathologically characterized by destructive alterations in pulmonary architectures as a result of persistent inflammation. However, alterations in the turnover of pulmonary cells are less well understood. This study was designed to examine whether the turnover of alveolar wall cells is altered in patients with emphysema. PATIENTS AND MEASUREMENTS: We obtained lung tissue specimens from patients with emphysema who had undergone lung volume reduction surgery (13 patients) as well as asymptomatic smokers (7 patients) and nonsmokers (9 patients) undergoing lung resections for solitary lung cancers. Paraffin-embedded lung tissue sections were evaluated for apoptosis and proliferation using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) or immunohistochemistry for Bax, proliferation cell nuclear antigen (PCNA), and topoisomerase IIalpha. Tissue sections were also immunostained for epithelial membrane antigen, surfactant protein A, and CD31. RESULTS: The percentages of alveolar wall cells undergoing apoptosis and proliferation of the total number of alveolar wall cells were significantly higher in patients with emphysema than in asymptomatic smokers and nonsmokers (p < 0.05). The percentage of TUNEL-positive alveolar wall cells was positively correlated with the percentage of PCNA-positive alveolar wall cells. Most of the TUNEL-positive and PCNA-positive cells were alveolar epithelial cells. CONCLUSIONS: These results suggest that the turnover of alveolar wall cells is enhanced in emphysematous lungs, compared to healthy lungs. Emphysema may be a dynamic disease process in which alveolar wall cell death and proliferation are repeated.     

Humic acid enhances cigarette smoke-induced lung emphysema in mice and IL-8 release of human monocytes

Tobacco smoke is the main factor in the etiology of lung emphysema. Generally prolonged, substantial exposure is required to develop the disease. Humic acid is a major component of cigarette smoke that accumulates in smokers’ lungs over time and induces tissue damage.

Objectives

To investigate whether humic acid pre-loading potentiates the development of cigarette smoke-induced lung emphysema in mice and increases IL-8 release by human monocytes.

Methods

C57BL/6J mice received humic acid or aqueous vehicle by tracheal installation on day 0 and day 7. From day 21 to day 84, the mice were exposed to cigarette smoke or clean air for 5 days/week. Twenty-four hours after the last exposure we determined leukocytes in lung lavage, heart hypertrophy and alveolar wall destruction. Human monocytes were incubated with cigarette smoke extract (CSE), humic acid or the combination overnight.

Results

Humic acid nor cigarette smoke caused alveolar wall destruction within two months. Interestingly, the combination did induce lung emphysema. Humic acid, cigarette smoke or the combination did not change leukocyte types and numbers in lung lavage fluid, but the combination caused peribronchiolar and perivascular lymphocyte infiltration. Humic acid treatment resulted in a high proportion of alveolar macrophages heavily loaded with intracellular granula. Humic acid also induces the release of IL-8 from human monocytes and enhances the CSE-induced IL-8 release.

Conclusions

Humic acid deposition in the lungs potentiates the development of cigarette smoke-induced interstitial inflammation and lung emphysema. Moreover, humic acid promotes IL-8 release from human monocytes. Since humic acid accumulates steadily in the lungs of smokers, this may provide an explanation for the natural history on late onset of this disease. The model described here offers a novel way to study emphysema and may direct the search for new therapeutic approaches.     

Computed tomography-quantified emphysema distribution is associated with lung function decline

Emphysema distribution is associated with chronic obstructive pulmonary disease. It is, however, unknown whether computed tomography (CT)-quantified emphysema distribution (upper/lower lobe) is associated with lung function decline in heavy (former) smokers. 587 male participants underwent lung CT and pulmonary function testing at baseline and after a median (interquartile range) follow-up of 2.9 (2.8-3.0) yrs. The lungs were automatically segmented based on anatomically defined lung lobes. Severity of emphysema was automatically quantified per anatomical lung lobe and was expressed as the 15th percentile (Hounsfield unit point below which 15% of the low-attenuation voxels are distributed (Perc15)). The CT-quantified emphysema distribution was based on principal component analysis. Linear mixed models were used to assess the association of emphysema distribution with forced expiratory volume in 1 s (FEV(1))/forced vital capacity (FVC), FEV(1) and FVC decline. Mean±sd age was 60.2±5.4 yrs, mean baseline FEV(1)/FVC was 71.6±9.0% and overall mean Perc15 was -908.5±20.9 HU. Participants with upper lobe-predominant CT-quantified emphysema had a lower FEV(1)/FVC, FEV(1) and FVC after follow-up compared with participants with lower lobe-predominant CT-quantified emphysema (p=0.001), independent of the total extent of CT-quantified emphysema. Heavy (former) smokers with upper lobe-predominant CT-quantified emphysema have a more rapid decrease in lung function than those with lower lobe-predominant CT-quantified emphysema.