AM J RESPIR CRIT CARE MED 1999;160:S17−S20.Cigarette smoking causes an inflammatory process in the central airways, peripheral airways, and lung parenchyma, even in smokers with normal lung function. The characteristics of this inflammatory process differ between smokers who develop chronic airflow limitation (COPD) and those who do not develop chronic airflow limitation: there is an increased infiltration of CD8-positive T lymphocytes in smokers with COPD. We examine whether airway inflammation alters with increasing severity of disease. When the disease becomes severe, a prominent neutrophilia occurs. The precise roles of the CD8+ T lymphocyte and the neutrophil in the pathogenesis of COPD still remain to be determined. Saetta M. Airway inflammation in chronic obstructive pulmonary disease.
Several studies have shown that cigarette smoking is associated with an airway inflammatory process (1-15), but the reason why, in a population of heavy cigarette smokers, only 15% of the subjects develop chronic obstructive pulmonary disease (COPD) (16) is unknown. In particular, it is still unclear whether the characteristics of the airway inflammatory process are different in smokers who develop COPD compared with those who do not develop COPD, and whether these characteristics change in severe disease.
I review first the literature showing that cigarette smoking causes airway inflammation. Then, in the second and third sections, I attempt to answer the following questions: (1) Is airway inflammation different in smokers who develop COPD and in smokers who do not develop COPD? (2) Does airway inflammation change with increasing disease severity?
Several studies have shown that cigarette smoking causes an inflammatory process in central airways (1-3), peripheral airways (4-10), and lung parenchyma (11). These studies have been performed mainly in smokers with normal FEV1.
In bronchial biopsies obtained from central airways (3), we found that smokers had an increased number of macrophages and T lymphocytes as compared with nonsmokers, while other inflammatory cells, e.g., neutrophils, eosinophils, and mast cells, were present in similar numbers in the two groups of subjects examined. It is noteworthy that we did not observe an increased number of neutrophils in bronchial biopsies of smokers, which contrasts with reports on bronchoalveolar lavage (17). A possible explanation for this discrepancy between the relatively low number of neutrophils observed in the airway wall and the high number of neutrophils reported in lavage is the rapid migration of neutrophils across the tissue into the lumen, so that the effect of accumulation of these cells is undetectable by tissue analysis, but quite detectable by analysis of lavage. It is also possible that the inflammatory process present in the airway lumen simply does not reflect the inflammatory process present in the airway wall, with the neutrophil being the predominant cell in the former, and macrophages and T lymphocytes being the predominant cells in the latter (18).
When we examined the peripheral airways in surgical specimens, we found that, compared with nonsmokers, smokers had greater inflammation in the airway wall, the level of which was significantly correlated with the destruction of the alveolar walls attached to the airways (alveolar attachments) (7). We then hypothesized a pathogenic role for airway inflammation in inducing destruction of alveolar attachments in smokers. It is possible that by-products of inflammatory cells weaken the alveolar tissue and facilitate its rupture, particularly at the point where the attachments join with the outer airway wall and where mechanical stress is probably maximal.
When we examined the lung parenchyma, we found that, as compared with nonsmokers, smokers had increased inflammation in the alveolar walls (11) that consisted predominantly of mononuclear cells, and was significantly correlated with the degree of parenchymal destruction (19).
To investigate the functional significance of these pathologic lesions, we then examined their relationship with the values of transpulmonary pressure at 90% of total lung capacity. We found that the indices of lung inflammation and destruction both around the peripheral airways (7) and in the overall parenchyma (11, 19) were significantly correlated with the loss of elastic recoil pressure of the lung in these subjects, supporting the important role of airway inflammation in the pathogenesis of loss of elasticity in smokers.
Most of the pathologic data we have seen have been obtained from smokers with normal FEV1, suggesting that cigarette smoking can elicit an early inflammatory reaction in the lung, even before COPD is established. This observation is supported by the findings of Niewoehner and coworkers (4), who showed that an inflammatory process is already present in the airways of young smokers who experience sudden death outside hospital.
We can conclude (1) that cigarette smoking causes airway inflammation even in smokers with normal lung function; (2) that the inflammation involves central airways, peripheral airways, and lung parenchyma, and (3) that it is related to the degree of parenchymal destruction.
All of the studies mentioned thus far do not distinguish between smokers who develop chronic airflow limitation and smokers who do not develop chronic airflow limitation. But we know from the literature that, in a population of heavy smokers, only 15% of the subjects develop chronic airflow limitation (16), and the characteristics that distinguish smokers who develop COPD from those who do not develop COPD remain unclear.
To investigate whether airway inflammation is different in smokers who develop COPD and in smokers who do not develop COPD, we examined surgical specimens obtained from two groups of smokers: one group of asymptomatic smokers with normal lung function (without COPD) and one group of smokers with symptoms of chronic bronchitis and mild chronic airflow limitation (with COPD) (10).
In peripheral airways, we measured the smooth muscle mass and the inflammatory cell infiltrate. We found that smokers with COPD had an increased smooth muscle mass as compared with smokers without COPD, which is in agreement with the results of Bosken and coworkers (20), suggesting the presence of airway remodeling in smokers who develop chronic airflow limitation. When we examined the differential cell counts, we observed that the only difference between the two groups of smokers was an increased number of CD8+ T lymphocytes in smokers with COPD (Figure 1) as compared with smokers without COPD, while the other inflammatory cells, including neutrophils, were similar in the two groups of smokers. CD8+ T lymphocytes not only were increased in these subjects, but were also correlated with the degree of airflow limitation (10).
These findings are in agreement with the results reported earlier by O'Shaughnessy and colleagues (21), who demonstrated an increased number of CD8+ T lymphocytes in the central airways of subjects with COPD and a correlation between the number of CD8+ T lymphocytes and the degree of airflow limitation. Taken together, these studies suggest that the inflammatory process present in central airways may reflect the inflammatory process present in peripheral airways in smokers with COPD, and that this inflammatory process consists predominantly of CD8+ T lymphocytes.
Traditionally, the major activity of CD8+ T lymphocytes has been considered the rapid resolution of acute viral infection (22), and viral infections are a frequent occurrence in patients with COPD (23). It is possible that an excessive recruitment of CD8+ T lymphocytes may occur in response to repeated viral infections in some smokers, and that this excessive response may damage the lungs of susceptible smokers (21).
We can conclude, therefore, that smokers who develop COPD have an increased number of CD8+ T lymphocytes in both central and peripheral airways as compared with smokers who do not develop COPD, supporting the important role of these cells in the pathogenesis of chronic airflow limitation in smokers.
All of the studies outlined above have examined smokers with a mild degree of airflow limitation. But we know from the literature that, when COPD is established, it may progress toward a severe stage (16).
To investigate whether airway inflammation alters with increasing disease severity, we have examined bronchial biopsies obtained from one group of smokers with symptoms of chronic bronchitis and severe chronic airflow limitation (with severe COPD), and from another group of asymptomatic smokers with normal lung function (without COPD) (24). In contrast to what we have seen in smokers with mild COPD, we have observed a prominent neutrophilia in smokers with severe COPD, when compared with smokers with normal lung function. Neutrophils were not only increased in these severely affected subjects, but also correlated with the degree of airflow limitation (24).
These findings show that, as the severity of airflow limitation increases, the number of neutrophils in the airway wall also increases, suggesting a role for these cells in the progression of the disease. This hypothesis is supported by the observation in surgical specimens that a prominent neutrophilia is present in bronchial glands of smokers who develop symptoms of chronic bronchitis and chronic airflow limitation (Figure 2) as compared with asymptomatic smokers with normal lung function (25). In further support of the association between neutrophilia and severity of disease, there is an increased number of neutrophils during exacerbations of chronic bronchitis (26, 27). It is possible that the neutrophilia represents a response to an altered milieu, perhaps infectious, in the airways of these subjects.
We can then conclude that, when COPD becomes severe, the pattern of bronchial inflammation changes and is characterized by a prominent neutrophilia.
There are interesting observations by Wenzel and colleagues (28) of possible relevance to the present report. These investigators have consistently shown significantly higher numbers of neutrophils in the airways of patients with severe asthma when compared with those with mild asthma and with normal control subjects. These findings, even though probably biased by glucocorticoid treatment of patients with severe asthma (29), invite speculation that in asthma, as in COPD, when the disease becomes severe, a prominent airway neutrophilia is present. The precise role of neutrophils in the development of the structural changes characteristic of the two well- distinguished diseases still remains to be investigated.
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