Emphysema - technical

Emphysema has been defined as abnormal permanent enlargement of airspaces distal to terminal bronchioles accompanied by destruction of their walls that lead to loss of lung elasticity and closure of small airways.

Emphysema is recognized as one of the main components of chronic obstructive pulmonary disease, the second one being inflammation of the airways, lung parenchyma, and pulmonary vasculature. This leads to small airway closure and air trapping with hyperinflation, which are responsible for the clinical features of exertional dyspnea, cough, and sputum production.

Different patterns of emphysema are recognized, however, suggesting possible different pathogenic processes within the lung. The centrilobular pattern of emphysema is most closely associated to cigarette smoking, whereas the panacinar pattern, which is characterized by a more even involvement of the acinus, is often associated with a1-antitrypsin deficiency.

Assessment of emphysema by high-resolution computed tomography scan has been shown to correlate with histologic and functional abnormalities. Smoking cessation, bronchodilators, and inhaled corticosteroids are the mainstay of therapy, although pulmonary rehabilitation and, in selected cases, lung volume reduction may improve pulmonary function and quality of life of these patients.


The Ciba Guest Symposium, later modified by Snider and others, defined emphysema as ‘‘abnormal permanent enlargement of airspaces distal to terminal bronchioles, accompanied by destruction of their walls without obvious fibrosis.’’ This definition emphasizes the destruction of the alveolar surface with a minimal reparative response in the lung matrix and the ability of this destructive process to reduce the gas-exchanging surface of the lung.

Pulmonary emphysema was first described by Laennec in 1834 from observations of the cut surface of postmortem human lungs that had been fixed by inflation. He postulated that lesions were due to overinflation of the lung that compressed capillaries, leading to atrophy of lung tissue. However, the observation more than a century later that emphysema could be produced experimentally by depositing the enzyme papain in the lung and the description of emphysema in patients with a1-antitrypsin (AAT) deficiency led naturally to the hypothesis that emphysema results from a proteolytic imbalance caused by cigarette smoking.

It is now recognized that emphysema is a part of a global disease known as chronic obstructive pulmonary disease (COPD). Many previous definitions of COPD emphasized the terms ‘emphysema’ and ‘chronic bronchitis’, but the recognition that COPD has both airway and airspace characteristics led to the common definition of the disease. The pathological hallmarks of COPD are inflammation of the large (bronchitis) and small airways (bronchiolitis), the lung parenchyma, and the pulmonary circulation, as well as the destruction of lung parenchyma (emphysema). The functional consequence of bronchiolitis and emphysema is airflow limitation. These lesions are associated with a chronic inflammatory response to a lifetime exposure to inhaled toxic gases and particles, mostly tobacco smoke, that involves cells of both the innate and the adaptive immune response.


In the 1950s, air pollution and airway infections were thought to be the major etiologic factors responsible for COPD. However, the prevalence of cigarette smoking in the United States peaked by the 1960s, and by then adequate cross-sectional epidemiologic evidence had accumulated for the Surgeon General’s advisory committee to state that ‘‘cigarette smoking is the most important of the causes of chronic bronchitis and increases the risk of dying from chronic bronchitis and emphysema.’’

The relation between cigarette smoking and emphysema shows a rough dose-response curve between packs per year and the presence of emphysema, but only approximately 40% of heavy smokers develop substantial lung destruction. However, this observation should not be confused with the fact that only 15–20% of people who smoke develop COPD, because emphysema is sometimes found in people who maintain normal lung function. Several endogenous (genetic background) and environmental factors increase the risk of COPD.


Current descriptions of COPD pathology include changes in large airways, small airways (bronchiolitis), alveolar space (emphysema), and pulmonary vasculature. The various lesions are a result of chronic inflammation in the lung, which in turn is initiated by the inhalation of noxious particles and gases such as those present in cigarette smoke.

Large airway changes consist of mucous gland enlargement and goblet cell hyperplasia. They are not believed to contribute directly to the airflow limitation in these patients because their contribution to the increased airway resistance that occurs in COPD is marginal.

In contrast, small airways (<2mm) are the sites of increased airway resistance in COPD. Changes that predispose to narrowing of the small airways include goblet cell hyperplasia, smooth muscle hypertrophy, excess mucus, edema, and inflammatory cellular infiltration. Subepithelial fibrosis with collagen deposition in the small airways appears to be the most critical factor in airway narrowing. Respiratory bronchiolitis may be of particular importance since mononuclear inflammatory cells may cause proteolytic destruction of elastic fibers in the respiratory bronchioles and alveolar ducts. The resulting narrowing of this structure seems to be involved in the early airflow obstruction in cigarette smoking related COPD. In addition, small airway patency is maintained by the surrounding lung parenchyma, which provides radial traction on bronchioles at points where alveolar septa attach. The loss of bronchiolar and alveolar attachments due to extracellular matrix destruction causes airway distortion and narrowing in COPD.

Alveolar space changes constitute the cornerstone of the term emphysema. They are due to chronic inflammation of alveolar walls and destruction with coalescence into larger alveolar spaces. Emphysema is therefore a structural abnormality of the lungs that affects the gas-exchanging airspaces (i.e., the respiratory bronchioles, alveolar ducts, and alveoli). Of note, the definition excludes enlarged airspaces caused by fibrosis to acknowledge that primary fibrotic processes can abnormally tether and enlarge airspaces.

However, recent data indicate that small airway fibrosis may be a major manifestation of COPD.

Emphysema is often classified into distinct pathological types, with centriacinar and panacinar being the most important.

Centriacinar emphysema is characterized by enlarged airspaces found initially in association with respiratory bronchioles, although in more severe cases virtually the whole acinar unit may be involved. In this pattern of emphysema, the focal nature of the lesions stands out against often apparently normal lung, and quite small lesions can be identified. This type of emphysema is most closely associated with tobacco smoking and is most often found in upper lobes of the lung, where separate lesions may coalesce to produce larger cavities.

Panacinar emphysema is characterized by abnormally large airspaces found evenly distributed across the acinar unit. Adjacent acinar units are usually involved to a similar degree, giving a confluent appearance to the cut surface of the lung, with extensive areas being involved. This type of emphysema is usually associated with AAT deficiency and is more common in the lower lobes.

The following are other types of emphysema:

  • Paraseptal emphysema, in which the abnormal airspaces run along the edge of the acinar unit but only where it abuts against a fixed structure, such as the pleura, a vessel, or a septum.
  • Scar or irregular emphysema, in which the emphysematous spaces are found around the margins of a scar. Because the scar may not be related to the anatomy of the acinar unit, this type of emphysema is not classified in relationship to the acinus.
  • Bullae are areas of emphysema that locally overdistend to produce a lesion that, if superficial, protrude on the pleural surface. By convention, only lesions more than 1 cm in diameter justify the description of bullae.

Pulmonary vasculature changes in COPD include perivascular inflammation, intimal thickening, muscularization of arterioles, in situ thrombosis, loss of capillaries and precapillary arterioles, and vascular congestion and stasis.

Structure–Function Correlations

Many studies have attempted to address the pathological changes of the small airways in smokers and their relationship to the flow limitation found in COPD (Table 3). Of special interest are studies comparing the airway changes in smokers with various degrees of emphysema and COPD to nonsmokers since they give an indication not only of the effects of smoking and emphysema but also of the effect of aging in the airways.

By studying smokers who had tests of pulmonary function done, including those reflecting the small airways, before undergoing resection for lung tumors, investigators at McGill University developed a pathological score to describe the microscopic changes in the small airways that allowed them to study the correlations between morphology and function. Specifically, they scored luminal occlusion, goblet cell metaplasia, squamous cell metaplasia, mucosal ulcers, muscle hypertrophy, inflammatory cell infiltrate, fibrosis, and pigment deposition of the airway wall in airways smaller than 2mm in diameter. The first abnormalities that could be seen in older smokers were changes in the epithelium, with squamous and goblet cell metaplasia and a chronic inflammatory infiltrate, and a slight increase in the connective tissue in the walls of the small airways. As the pathologic and functional abnormalities progressed, the cellular inflammatory infiltrate changed little, but there was a progressive increase in the connective tissue pigment and muscle in the airway wall.

When the physiological measurements reflecting small airway abnormalities, such as nitrogen washout test, volume of isoflow, and Vmax50, and other function tests, such as the percentage of forced vital capacity in 1 s (FEV1/FVC), midflow rate, and residual volume, were compared to the pathological score, all measurements showed a progressive deterioration as the score for the morphological abnormalities increased, but only the group with the most severe small airway score demonstrated a substantial amount of emphysema. The striking correlation between the progression of physiological impairment and the degree of small airway disease suggested that inflammatory changes of the small airways made an important contribution to the functional deterioration seen in COPD even in the presence of emphysema. Furthermore, in subjects with a normal FEV1/ FVC ratio, two tests of small airway function, the slope of phase III of the nitrogen washout and the volume of isoflow of the air–helium flow volume loops, were able to detect mild abnormalities of the small airways when spirometric tests were normal.

Hogg and colleagues confirmed these findings by studying lung tissue from patients with different degrees of airflow limitation according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification. They showed that progression of COPD is associated with the accumulation of inflammatory mucous exudates in the lumen and infiltration of the wall by innate and adaptive inflammatory immune cells that form lymphoid follicles.

These changes are coupled to a repair or remodeling process that thickens the walls of these airways.

Clinical Features

Symptoms, signs, and the diagnosis of COPD are described elsewhere. See: COPD. However, the radiologic assessment of emphysema deserves special consideration.

In 1978, Thurlbeck and Simon described criteria for the diagnosis of emphysema using the chest radiograph. These were based on indications of hyperinflation and vascular pruning and showed only a moderate correlation with macroscopic emphysema as assessed by the picture matching technique. When computed tomography (CT) scans became available, it became possible to extract quantitative data on lung density. When quantitative histologic assessment is compared with quantitative CT assessment, a good correlation is found even within the range of those showing normal age change and early emphysema. However, attempts to use qualitative grading, scoring, or picture matching techniques have shown poorer correlation with lung function than actual quantitative measurements.

The CT scan, particularly high-resolution CT scan (HRCT), can detect the extent and severity of emphysematous lung by directly visualizing areas of destroyed lung, identified as areas of low attenuation without visible walls (Figure 4). HRCT scans also allow reliable distinction of centrilobular emphysema from other causes of airflow obstruction, such as bronchiectasis and constrictive bronchiolitis.


COPD is characterized by chronic inflammation throughout the airways, parenchyma, and pulmonary vasculature. The intensity and cellular and molecular characteristics vary as the disease progresses. Over time, inflammation damages the lungs and leads to the pathologic changes characteristic of COPD. In addition to inflammation, two other processes thought to be important in the pathogenesis of COPD are an imbalance of proteinases and antiproteinases in the lung and oxidative stress.


The recognition that inflammation plays a key role in the pathogenesis of COPD is now so widespread and considered so important that it has led to the inclusion of the term ‘abnormal inflammatory response’ in the disease definition. Thus, the GOLD guidelines define COPD as a ‘‘disease state characterized by not fully reversible airflow limitation that is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases.’’ It is now believed that the establishment of COPD is associated with further enhancement of the inflammatory response already present in the small airways of normal smokers, which is paralleled by the development of structural abnormalities. These events are reflected in the progressive deterioration of pulmonary function.

The overall cellular inflammatory infiltrate in smokers’ airways was described by Finkelstein and coworkers, who carefully differentiated and quantitated the number of cells per millimeter of airway wall in smokers, categorized according to the type of emphysema, and nonsmokers’ lungs obtained at surgery. They found a large number and a wide variation in the number of cells between cases and also within the airways of the same patients. Patients with centrilobular emphysema tended to have more inflammatory cells than patients with panlobular emphysema. It can be concluded based on their results that the peripheral airways of cigarette smokers exhibit a large number and variety of inflammatory cells and that the extent of the cellular infiltration shows a wide variability, indicating that inflammation is unevenly distributed throughout the small airways.

Other authors phenotyped the T lymphocytes found in airway biopsies and lung specimens and characterized them as predominantly CD8þ T cells. Interestingly, CD8þ T cells not only were increased in these subjects but also correlated negatively with the degree of airflow limitation. This increase in lymphocytes is also associated with an increase in the socalled bronchial-associated lymphoid tissue (BALT), which is rarely found in healthy nonsmokers, is more frequent in cigarette smokers, and shows a further sharp increase in patients with severe (GOLD 3) and very severe (GOLD 4) COPD. This increase in lymphocyte subtypes and the appearance of BALT at this stage of COPD suggest the development of an adaptive immune response that may be driven by microbial colonization and infection, among others.

The finding of increased numbers of T lymphocytes and especially CD8þ T cells only in smokers who develop COPD is intriguing and supports the notion that T-cell inflammation in the lungs is important and may be essential for the development of COPD, raising the hypothesis of the role of autoimmunity in COPD.

Elastase–Antielastase Imbalance

In 1963, Laurell and Eriksson first described the association between emphysema and AAT deficiency, the primary inhibitor of the neutral serine proteinase neutrophil elastase (NE). With respect to AAT, we now know that patients with the deficiency have mutations in the AAT gene. The most common mutation is the Z mutation, which converts Glu to Lys. These mutations impair secretion of the protein from hepatocytes, resulting in markedly decreased circulating levels of this serine proteinase inhibitor. PiZ AAT is slightly less effective as an inhibitor due to its slower rate of association with NE than normal PiM AAT. These genetic changes allow NE to act relatively unopposed, thereby shifting the balance in favor of elastolysis.

Other proteases, such as metalloproteinase-9 and -12 (MMP-9 and -12, respectively), have been shown to be related to the development of emphysema throughout transforming growth factor beta activation and fibrosis. Tissue inhibitor of metalloproteinase- 3 (TIMP-3) deficiency leads to a combination of developmental airspace enlargement and progressive destructive emphysema in adults, supporting the role of MMPs in COPD.

Oxidative Stress

Cigarette smoke and inflammatory cells have the capacity to produce reactive oxygen species, and they have been postulated to play a variety of roles in the pathogenesis of emphysema. One intriguing finding was that cigarette smoke can oxidize a methionine residue in the reactive center of a1PI, inactivating it and thus altering the elastase–antielastase balance. Oxidants cannot degrade extracellular matrix but may modify elastin, making it more susceptible to proteolytic cleavage. MacNee and others have found that intracellular oxidation of IK-kb promotes its ubiquitination and the release of free nuclear factor kappa B (NF-kB), which translocates to the nucleus, resulting in transcription of proinflammatory genes such as interleukin-8 and tumor necrosis factor alpha. Barnes and colleagues found that cigarette smoke oxidizes and inactivates histone deacetylase 2 (HDAC2), which acts to counter histone acetylase. Acetylation of histone unwinds chromatin, allowing transcriptional complexes to bind to DNA. Thus, in the absence of HDAC2, RNA polymerase II and NFkB form a proinflammatory transcription complex. This may explain steroid resistance in COPD because the activated glucocorticoid receptor acts to translocate HDAC2 to the nucleus, which keeps the chromatin wound inactive.

Voelkel and colleagues hypothesized that oxidative stress has a central role in alveolar septal cell apoptosis and emphysema induced by vascular endothelial growth factor (VEGF) receptor blockade. Compared to control animals, rats treated with the VEGF receptor blocker SU5416 showed increased alveolar enlargement, alveolar septal cell apoptosis, and expression of markers of oxidative stress, all of which were prevented by the superoxide dismutase mimetic M40419.

Animal Models of Emphysema

Many investigators have tried to produce an animal model of emphysema by destroying the elastic fibers in the lung of different animals using a variety of proteinases, following the first description by Gross in 1965, who instilled papain into the lungs of rodents and found emphysema. However, none of them fully reproduce the full picture of pathologic changes seen in patients with COPD.

For hypothesis testing in relation to pathogenic mechanisms of human COPD, animal models representing the various patterns of lung destruction and function observed in humans are needed. Because the major environmental factor that predisposes patients to COPD is long-term cigarette smoking, a cigarette smoke exposure model would be advantageous. A variety of animals have been exposed to cigarette smoke, including dogs, rabbits, guinea pigs, and rodents. The results in terms of lung pathology have been variable. To take advantage of the defined genome and the well-established methods of modulating gene expression, murine models of cigarette smoke exposure have been evaluated. Although airspace enlargement has been observed in these murine models, little attention has been paid to how well this simulates the varied pathologic features in smokingassociated emphysema of humans.

Recent trends in molecular genetics and advances in molecular physiology make the mouse an ideal investigative model for determining genomic variants affecting susceptibility to COPD. Mice are susceptible to the development of emphysema, and several strains have been described that develop emphysema after prolonged cigarette smoke exposure. Guerassimov and colleagues characterized different phenotypes of mice in response to cigarette smoke in different strains with and without reduced AAT levels and serum elastase inhibitory capacity.

Interestingly, Voelkel and colleagues described an animal model of autoimmune emphysema by injecting intraperitoneally xenogeneic endothelial cells in rats, which may help to sustain the role of autoimmunity in the pathogenesis of emphysema.


COPD is managed according to the severity of the disease in a stepwise approach, with a progressive escalation of therapy as the disease progresses. Smoking cessation, pharmacological treatment with bronchodilators and inhaled corticosteroids, and oxygen therapy are the mainstay of treatment for COPD.

Nonpharmacologic management of emphysema involves pulmonary rehabilitation, lung volume reduction, and, in selected severe cases, lung transplantation.

Pulmonary Rehabilitation

The goals of rehabilitation in COPD are multifactorial, including decrease and control of respiratory symptoms, increase in physical capacity, improvement in health status, reduction of the psychological influence of physical impairment and disability, prevention of complications and exacerbations, and, ultimately, prolongation of life. There is much evidence that rehabilitation improves dyspnea on exertion and that associated with daily activities in COPD. Favorable outcomes have been reported after pulmonary rehabilitation in maximum exercise tolerance, peak oxygen uptake, endurance time during submaximal testing, functional walking distance, and strength of peripheral and respiratory muscles. Pulmonary rehabilitation also results in a clinically significant improvement in disease-specific and general measures of quality of life. The effect size of pulmonary rehabilitation largely exceeds what can be achieved by the best pharmacological therapy. This intervention is therefore judged to be evidence based with respect to both exercise tolerance and symptoms of dyspnea and fatigue. These effects are longlasting (41 year) and not necessarily related to improvements in exercise ability.

Lung Volume Reduction

Lung volume reduction surgery (LVRS) consists of the removal of the most damaged parts of the lungs in selected patients with emphysema, particularly those with upper lobe emphysema and poor exercise capacity after a full rehabilitation program. Initial reports showed that LVRS appeared to produce functional benefits, including increased FEV1, reduced total lung capacity and functional residual capacity, and improved function of respiratory muscles. However, uncertainty about morbidity and mortality, the occurrence, magnitude, and duration of benefits, and preoperative predictors of benefit led to multicenter, randomized clinical trials.

The National Emphysema Treatment Trial used mortality and maximum exercise capacity 2 years after randomization as the primary outcomes. Overall mortality did not differ in this study between patients undergoing LVRS and those assigned medical therapy only. Exercise capacity after 24 months had improved by more than 10W in 16% of patients in the surgery group compared to 3% of patients in the medical therapy group. Patients assigned surgery were significantly more likely than those assigned medical therapy to have improvements in the distance walked in 6 min, the percentage predicted values for FEV1, general and health-related quality of life, and degree of dyspnea. After interim analyses, patients with FEV1 20% or less of the predicted value and either homogeneous emphysema or a diffusing capacity of carbon monoxide that was 20% or less of the predicted value had a high risk of death after LVRS, with little chance of functional benefit. The National Emphysema Treatment Trial found that patients with predominantly upper lobe emphysema and low exercise capacity had lower mortality after LVRS than the corresponding medical therapy group. Cost-effectiveness analysis shows that LVRS is costly compared to medical therapy.

Currently, the use of endobronchial valve placement to reduce lung volume endoscopically is being investigated. Preliminary results indicate that it can improve lung volumes and gas transfer in patients with COPD and prolong exercise time by reducing dynamic hyperinflation.

Lung Transplantation

Pulmonary emphysema was initially thought to be a contraindication to lung transplantation, but smoking-related and AAT deficiency emphysema have become the most common indication for pulmonary transplantation. Patients with diffuse disease, low FEV1 (o20% predicted), hypercapnia (PaCO247.3 kPa), and associated pulmonary hypertension are directed toward lung transplantation. The advantages of this approach have to be carefully balanced against the well-known disadvantages. Complete replacement of the diseased and nonfunctioning lungs can contribute to a striking improvement in pulmonary function and exercise tolerance, but the paucity of available donor lungs has created a long waiting list, the operation is associated with initial morbidity and mortality, and there is a risk of chronic allograft dysfunction or bronchiolitis obliterans syndrome. Furthermore, with strict adherence to selection criteria, very few patients with emphysema are candidates for any surgical therapy.

Further Reading

Agusti A, MacNee W, Donaldson K, and Cosio M (2003) Hypothesis: does COPD have an autoimmune component? Thorax 58(10): 832–834.

Barnes PJ (2000) Chronic obstructive pulmonary disease. New England Journal of Medicine 343(4): 269–280.

Barnes PJ and Stockley RA (2005) COPD: current therapeutic interventions and future approaches. European Respiratory Journal 25: 1084–1106.

Calverley PM andWalker P (2003) Chronic obstructive pulmonary disease. Lancet 362(9389): 1053–1061.

Cosio MG and Majo J (2002) Inflammation of the airways and lung parenchyma in COPD: role of T Cells. Chest 121(supplement 5): 160S–165S.

Fishman AP (2005) One hundred years of chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 171(9): 941–948.

Fishman A, Martinez F, Naunheim K, et al. (2003) A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. New England Journal of Medicine 348(21): 2059–2073.

Flaherly KR and Martinez FJ (2000) Lung volume reduction surgery. Clinics in Chest Medicine 21(4): 835.

Geddes D, Davies M, Koyama H, et al. (2000) Effect of lungvolume- reduction surgery in patients with severe emphysema. New England Journal of Medicine 343(4): 239–245.

Hogg JC (2004) Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet 364(9435): 709–721.

Hogg JC, Chu F, Utokaparch S, et al. (2004) The nature of smallairway obstruction in chronic obstructive pulmonary disease. New England Journal of Medicine 350(26): 2645–2653.

Mahadeva R and Shapiro SD (2002) Chronic obstructive pulmonary disease: experimental animal models of pulmonary emphysema. Thorax 57(10): 908–914.

Pauwels RA, Buist AS, Calverley PM, Jenkins CR, and Hurd SS (2001) Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/ WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) workshop summary. American Journal of Respiratory Critical Care Medicine 163(5): 1256–1276.

Shapiro SD and Ingenito EP (2005) The pathogenesis of chronic obstructive pulmonary disease: advances in the past 100 years. American Journal of Respiratory Cell and Molecular Biology 32(5): 367–372.

Sutherland ER and Cherniack RM (2004) Management of chronic obstructive pulmonary disease. New England Journal of Medicine 350(26): 2689–2697.

Wouters EF (2004) Management of severe COPD. Lancet 364(9437): 883–895.