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What Is the Pathophysiology of COPD?

Philadelphia, PA: Elsevier Ltd; chap Harron, Jr. Editorial team.

Lung disease. There are three main types of lung disease: Airway diseases -- These diseases affect the tubes airways that carry oxygen and other gases into and out of the lungs. They usually cause a narrowing or blockage of the airways. Airway diseases include asthma , COPD and bronchiectasis.

People with airway diseases often say they feel as if they're "trying to breathe out through a straw. Scarring or inflammation of the tissue makes the lungs unable to expand fully restrictive lung disease. This makes it hard for the lungs to take in oxygen and release carbon dioxide. People with this type of lung disorder often say they feel as if they are "wearing a too-tight sweater or vest. Pulmonary fibrosis and sarcoidosis are examples of lung tissue disease. Lung circulation diseases -- These diseases affect the blood vessels in the lungs.

They are caused by clotting, scarring, or inflammation of the blood vessels. They affect the ability of the lungs to take up oxygen and release carbon dioxide. These diseases may also affect heart function. On the one hand, comorbidities may dramatically affect deterioration of symptoms and health status in patients with COPD; conversely, airflow limitation, and particularly hyperinflation and gas exchange abnormalities, may considerably affect cardiac function.

It is important to highlight that inflammation is not confined within the lung in patients with COPD, and increased levels of inflammatory mediators in the circulation may contribute to worsening comorbidities such as ischemic heart disease, heart failure, anemia, metabolic syndrome, renal disease and depression [ 29 ].

Furthermore, the presence of chronic inflammation may be a key element in the association between COPD and lung cancer, one of the most frequent comorbidities and cause of death in patients with COPD [ 30 ].

The mechanisms connecting the systemic inflammation to local responses within the lung are as of yet poorly understood, but this is an area of intense research where important advances are eagerly expected. In the peripheral airways of smokers with established COPD, several pathological changes have been described that can result in the narrowing of the airway lumen and the loss of the tethering function of the lung parenchyma, thus promoting a reduction of expiratory flow.

These pathological lesions include an inflammatory cell infiltrate, goblet-cell metaplasia, squamous-cell metaplasia, fibrosis and an increased smooth-muscle mass, due to hypertrophy and hyperplasia of smooth-muscle cells tables 1 , 2.

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Pathology of Lung Disease

Each of these components will be discussed below. The characterization of the inflammatory cell subtypes infiltrating peripheral airways has identified differences between smokers who do or do not develop COPD. If this were the case, an immunological reaction developing in some smokers might be the turning point from early nonspecific inflammation to subclinical and then clinical COPD [ 19 ]. Inflammation, per se, may be responsible for mild airflow limitation, and it has been suggested that it may lead to functional bronchiolar constriction by releasing mediators of inflammation that may act directly on bronchiolar smooth muscle.


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Chronic inflammation would, in turn, produce other changes, such as fibrosis of the airway, and could increase the smooth muscle — either directly as a result of inflammation or indirectly as a result of chronically increased muscle tone. These changes, by increasing the thickness of the airway wall, will promote airway narrowing and airflow limitation. Finally, inflammation of the airway could play an important role in the destruction of the alveolar walls attached to the airway alveolar attachments , and the decrease in these attachments would contribute further to airflow limitation by deforming and narrowing the airway lumen.

The epithelial layer plays an extremely important role in the normal function and regulation of the airways.

Obstructive Lung Diseases

Cigarette smoking can damage the airway epithelium, inducing mucosal ulcers and squamous- and goblet-cell metaplasia [ 24 ]. A significantly increased number of mucus-secreting goblet cells can be seen in the peripheral airway epithelium of smokers with COPD. This goblet-cell metaplasia can have important functional consequences, potentially contributing to the development of smoking-induced airflow obstruction in at least two ways: first, by producing an excess of mucus which could alter the surface tension of the airway lining fluid, rendering the peripheral airways unstable and facilitating their closure [ 4 ] and second, by inducing luminal occlusion through the formation of mucous plugs in the peripheral airways [ 24 ].

Indeed, luminal occlusion by mucous and inflammatory exudate plugs are frequently observed in smokers with COPD [ 32 ], and neutrophils, which are not usually found within the airway wall, are increased in their peripheral airway epithelium [ 36 ]. As neutrophil elastase is a remarkably potent secretagogue, it has been proposed that the location of neutrophils within the epithelium is crucial for the activation of the secretory function of goblet cells in smokers. While airway obstruction may be induced by excessive mucus production from the numerous goblet cells in the peripheral airways, it remains controversial whether or not chronic bronchitis due to mucus hypersecretion in the bronchial glands of the central airways contributes to the development of functional abnormalities.

For many years, chronic bronchitis was considered irrelevant, but more recent studies have demonstrated an association between chronic mucus hypersecretion, FEV 1 decline and COPD morbidity [ 37 , 38 ], suggesting that this clinical condition, when present, should not be ignored. When the amount of smooth muscle is measured in the peripheral airways of smokers with or without COPD, an increased area occupied by smooth muscle is found in those with COPD. Increase in smooth muscle correlates with the degree of airflow limitation; the greater the amount of smooth muscle, the lower the FEV 1 and the more severe the airway obstruction [ 25 ].

So, increased smooth-muscle mass is an important component of airway wall thickening, which can be due to several mechanisms including hypertrophy and hyperplasia, possibly due to the activity of inflammatory mediators, cytokines and growth factors. The airways of smokers can react to nonspecific stimuli by constricting, and this results in increased resistance and decreased FEV 1.

Whether hyperresponsiveness is a primary event that might contribute to the natural history of COPD or is a consequence of the already decreased airway dimensions is still an open question. Regardless of the mechanism, the abnormalities found in the airways of smokers, such as epithelial damage and chronic inflammation, could contribute to the constriction of even a normal airway smooth muscle [ 39 ]. The major functional consequence of the increase in smooth-muscle mass is that, in airways with thickened walls, the same degree of smooth-muscle shortening may cause considerably greater lumenal narrowing than in the normal airways [ 40 ].

Another important component of remodeling is fibrosis of the airway wall. It has previously been reported that cigarette smoke induces oxidative stress in human lung fibroblasts, which may then initiate a process of repair and collagen deposition [ 41 ]. Furthermore, the interaction between fibroblasts and inflammatory cells may also play a role in fibrotic remodeling. Along with this is the observation that mast cells, which have important profibrotic and prorepair properties, are increased in the airways of smokers with COPD, particularly in those with centrilobular emphysema [ 42 ].

Fibrosis, along with an increased airway smooth muscle and other inflammatory components, ought to increase the airway wall thickness and change the mechanical characteristics of the airway to decrease the luminal diameter. That this is indeed the case was shown by Wright et al. In the context of a disease such as COPD, it is well conceivable that the pathological changes observed in small airways are associated with an attempt to repair, resulting in fibrosis and thickening of the airway wall [ 45 ].

In line with this hypothesis, Hogg et al. Inflammation, fibrosis and smooth-muscle hypertrophy, by increasing the thickness of the airway wall, may facilitate uncoupling between airways and parenchyma, therefore promoting airway closure. In addition, airway wall inflammation could contribute to the destruction of alveolar attachments i.

This hypothesis is supported by the observation that, in smokers, the destruction of alveolar attachments is correlated with the degree of inflammation in the peripheral airways [ 46 ]. This finding suggests a pathogenetic role for airway inflammation in inducing the destruction of alveolar attachments. It is possible that mediators released by inflammatory cells may weaken the alveolar tissue and facilitate its rupture, particularly at the point where the attachments join the airway wall and the mechanical stress is maximal.

Note that the airway wall is thin, the lumen is wide open and that intact alveoli are attached along its circumference. The airway wall is thickened, with an important component of airway smooth muscle and fibrosis, and the majority of the alveolar attachments along its circumference are broken. Once the pathological changes in the airways are established, the striking correlation between the progression of physiological impairment and the degree of small airway disease suggests that inflammation of the small airways makes an important contribution to the functional deterioration seen in COPD, even in the presence of emphysema.

In patients with severe COPD, an amplification of the inflammatory response in the peripheral airways has been demonstrated, with a nearly 3-fold increase in the number of leukocytes, particularly of T lymphocytes and macrophages, suggesting that the inflammation initiated by cigarette smoking worsens as airflow deteriorates [ 47 , 48 ]. This worsening airway inflammatory process is correlated with the degrees of airflow limitation, lung hyperinflation, CO diffusion impairment and radiological emphysema, suggesting a role for this inflammatory response in the clinical progression of the disease [ 47 ].

A similar amplification of the inflammatory response was observed in the lung parenchyma of patients with severe emphysema by Retamales et al. These results confirm the pioneer observations of Nagai et al. In their study, flow rates correlated with the degree of macroscopic emphysema, but also with the degree of deformity of respiratory bronchioles, indicating that decreases in flow were secondary to both emphysema and airway obstruction.

Of note in that study is that, for the same degree of airflow limitation, smokers with lesser amounts of emphysema had more diseased small airways and vice versa , pointing to the heterogeneity of the pathophysiology of COPD, which is reflected in the heterogeneity in the clinical presentation.

Moreover, in patients in the most severe stages of COPD, inflammatory cells in the airway wall are observed in well-organized lymphoid follicles, that represent tertiary lymphoid structures specialized in antigen presentation [ 32 ]. Sequence analysis of rearranged immunoglobulin genes in individual B cell clones in these lymphoid follicles revealed the presence of clonally related B cells, suggesting an antigen-driven selection process.

Some authors suggested that these follicles represent an adaptive immune response which may develop in relation to microbial colonization and infection, which are a frequent occurrence in the later stages of COPD [ 32 ]. However, the absence of bacterial and viral products in the follicles prompts other authors to suggest that these oligoclonal B cells may arise in response to lung auto-antigens [ 52 ]. Indeed, there is increasing evidence that autoimmunity may play a role in the pathogenesis of COPD.

This hypothesis was first raised based on the observation that lymphocytes are the predominant cells infiltrating the lung tissue of patients with COPD and that their numbers are strongly related to the apoptosis of structural cells and lung function impairment. Currently, there is circumstantial, indirect and direct evidence of the involvement of cellular and humoral immune responses in the lung damage of COPD, possibly supported by the recognition of pulmonary self-antigens modified by cigarette smoking and the failure of mechanisms regulating immunological tolerance [ 19 ].

Nevertheless, no direct cause-effect relationship linking COPD to autoimmune damage has of yet been established, and further studies are required to investigate this important issue. In conclusion, in this review we have seen how the normal structure of the small airways is reached through development, how it is affected by the insult from cigarette smoke and how it is further modified in parallel with the establishment and progression of airflow limitation.

These observations highlight the complexity of COPD and its pathophysiology and points to the importance of studies correlating the morphology and function in COPD, the basis for our present understanding of the pathophysiology of the small airways. Copyright: All rights reserved.

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