American Journal of Respiratory and Critical Care Medicine

The airflow obstruction in chronic obstructive pulmonary disease (COPD) occurs mainly at the level of the small airways. In order to investigate the effect of smoking on small-airway submucosal immunopathology, we used immunohistochemistry in peripheral lung sections obtained at surgery from a group of smokers (n = 22) and from a group of nonsmokers (n = 22) that contained both ex-smokers (n = 17) and lifelong nonsmokers (n = 5). Subjects were also divided into those with (n = 19) and those without (n = 20) airflow obstruction. We found an increase in total eosinophils (p = 0.001) and activated eosinophils (p = 0.010), an increase in the CD8+/CD3+ cell ratio (p = 0.003), and a decrease in the CD4+/CD8+ cell ratio (p = 0.005) among cells infiltrating the small-airway submucosa in an area 50 μ m deep to the basement membrane in smokers as compared with nonsmokers. There was also an increase in neutrophils (p = 0.019) when smokers were compared with lifelong nonsmokers. Neutrophil numbers correlated with numbers of eosinophils (p = 0.0003, r = 0.58). Furthermore, the CD8+/CD3+ cell ratio was related to pack-years smoked (p = 0.016, r = 0.36), months since smoking cessation (p = 0.003, r = 0.47), and number of infiltrating eosinophils (p = 0.007, r = 0.43) and neutrophils (p = 0.004, r = 0.44). These findings suggest that smoking induces movement of an inflammatory infiltrate into the submucosa of the small airway, the location of the increased resistance to airflow in COPD.

Smoking is the major cause of chronic obstructive pulmonary disease (COPD), a disease characterized by fixed airflow obstruction (1). However, only 20% of smokers eventually develop clinically significant COPD (2). This suggests that host factors may be involved in the pathogenesis of this condition, and that it is important to differentiate changes induced by smoking per se from changes associated with the development of obstruction. Cigarette smoking is known to produce alterations in inflammatory cell populations in peripheral blood, bronchoalveolar lavage fluid (BALF), and in the airway mucosa that are independent of airflow obstruction. Studies have detected an increase in total leukocyte numbers, an increased CD8+-cell subpopulation, and a reduced CD4+/CD8+ cell ratio in the peripheral blood of smokers as compared with nonsmokers (3). Studies of the cellular component of BALF have shown an increase in alveolar macrophages (AM), neutrophils, and T lymphocytes, with a reduced CD4+/CD8+ cell ratio in smoking individuals (4, 5). Bosken and colleagues have shown by immunohistochemical analysis that smokers demonstrate an increase in infiltrating neutrophils into the small-airway submucosa (6).

The fixed airways obstruction characteristic of COPD results from an increase in resistance in the small airways (< 3 mm diameter) of the lung (7). Simple staining techniques have shown that airway remodelling and an inflammatory infiltrate in the small airways are associated with airflow obstruction in COPD (8-10). More recent studies, done with immunohistochemistry to investigate the nature of the inflammatory infiltrate in COPD, have examined biopsies taken from the larger airways visible on flexible bronchoscopy. Other studies have attempted to examine the small airways indirectly by analyzing the phenotype of cells obtained at bronchoalveolar lavage (BAL). Studies of the large airways in subjects with COPD have revealed an increase in the number of T lymphocytes, macrophages, and eosinophils infiltrating the epithelium and submucosa (11-16). Data from these studies have suggested that T lymphocytes are predominantly of the CD8+ phenotype, and that the infiltrating eosinophils are located deep within the submucosa and are not degranulated. These observations support the view that the immunopathology of COPD is distinct from that of asthma, in which activated CD4+ T lymphocytes predominate (17). Studies with BAL have produced conflicting results, with the predominant finding in most studies being an increase in the neutrophil population that has correlated with disease activity in some studies (4, 15, 18, 19).

There is little direct information about the effects of smoking on the immunopathology of the small airways. Only one study has examined the immunohistochemistry of the small airways in patients with fixed airflow obstruction (6). In the present study we set out to test the hypothesis that smoking per se alters the profile of the small-airway submucosal inflammatory cell infiltrate, and that this alteration might differ from the profile seen in smoking-related airflow obstruction.

Subjects

We studied 44 patients, including smokers, ex-smokers, and lifelong nonsmokers undergoing lung or lobe resection for peripheral lung masses (Table 1). Subjects were excluded if they had a history of asthma, eczema, or allergic rhinitis. All subjects underwent spirometry (PulmoLink Partn'Air 5500; Medisoft, Dinant, Belgium) within 2 wk prior to surgery, and were excluded if reversibility of FEV1 with 1 mg inhaled terbutaline, assessed after 15 min, was greater than 15% of the initial value of FEV1. Subjects also had skin-prick tests with a battery of common aeroallergens (ALK, Horsholm, Denmark), and were excluded if any reaction was greater than 2 mm. The study was approved by the Guy's and St. Thomas' Hospitals Ethics committees. All subjects gave written informed consent.

Table 1. CHARACTERISTICS OF GROUPS*

nMalesAgeFEV1 Pack-years
Obstructed airflow191268 ± 263 ± 1.645 ± 3.9
Nonobstructed airflow201062 ± 293 ± 2.063 ± 5.9
Smokers221263 ± 277 ± 4.057 ± 5.4
Nonsmokers221365 ± 285 ± 3.440 ± 5.4

*Data are expressed as mean ± SEM.

Smokers and ex-smokers were divided into a group with airflow obstruction whose FEV1 was less than 80% predicted (n = 19, age: 68 ± 2 yr [mean ± SEM], FEV1 = 63 ± 1.6% predicted [mean ± SEM]) and a group without airflow obstruction whose FEV1 was greater than 80% predicted (n = 20, age: 62 ± 2 yr, FEV1 = 93 ± 2% predicted). For analysis, all subjects were also divided into smokers (n = 22, age: 63 ± 2 yr, FEV1 = 77 ± 4% predicted) and nonsmokers (n = 22, age: 65 ± 2 yr, FEV1 = 85 ± 3.4% predicted). The nonsmoking group included a group of lifelong nonsmokers (n = 5, age: 58 ± 7 yr, FEV1 = 98 ± 9% predicted) and a group that had ceased smoking two or more months previously (n = 17, age: 68 ± 2 yr, FEV1 = 81 ± 3% predicted).

Immunohistochemistry

An average of 5.7 ± 0.6 (mean ± SEM) 1-cm2 blocks of tissue were taken from the periphery of the lung from each subject and immediately snap frozen in ornithyl carbamyltransferase (OCT) embedding medium (Miles, Elkhart, IN) in isopentane (BDH, Poole, UK) cooled over liquid nitrogen. Samples were stored at −70° C. From the stored blocks, 5 μm frozen sections were cut and examined with hematoxylin and eosin (H&E) staining until a section containing an adequate number of airways was obtained. Consecutive 5 μm frozen sections were then cut and used for immunohistochemistry. Two consecutive sections from each subject were included in each staining run, one being stained for the epithelial marker cytokeratin in order to identify small airways, and the other being stained with one of the cell markers. An average of 6.8 ± 0.7 (mean ± SEM) airways were identified in each section, and one section from each patient was analyzed for each immunohistochemical cell marker. All airways in a section were counted, and the total submucosal area evaluated was 0.74 ± 0.9 mm2 (mean ± SEM) in each subject. Average intrasubject variability between airway submucosal cell counts was 26 ± 2.45%. Power analysis revealed that adequate numbers of sections were studied to ensure a 95% chance of detecting a twofold increase in cell numbers between groups.

Immunohistochemistry was performed as previously described (20), using the avidin–biotin complex. Mouse monoclonal IgG1 primary antibodies were used for cell identification as follows: anti-CD3 (DAKO, High Wycombe, UK), a pan-T lymphocyte marker, used at 1:50 dilution; anti-CD4 (DAKO), used at 1:50 dilution; anti-CD8 (DAKO), used at 1:50 dilution; EBM11 (DAKO), a panmacrophage marker recognizing CD68 and used at 1:100 dilution; NP57 (DAKO), an antihuman neutrophil elastase (NE) antibody to identify neutrophils, used at 1:600 dilution; BMK13 (Cymbus Bioscience Ltd, Chilworth, UK), a paneosinophil marker recognizing major basic protein (MBP), used at 1:40 dilution; EG2 (Pharmacia, Uppsala, Sweden), a marker for activated eosinophils, recognizing eosinophilic cationic protein (ECP) and used at 1:100 dilution; ACT-1(DAKO), a marker for activated T cells, recognizing the IL-2 receptor (CD25) and used at 1:50 dilution; and CAM 5.2 (Becton Dickinson, San Jose, CA), a marker for epithelial cells, recognizing cytokeratin and used at 1:200 dilution for identification of small airways and as a positive control. A biotinylated rabbit antimouse antibody (DAKO) was used as a secondary antibody at a dilution of 1:400.

Endogenous biotin and peroxidase activity was abolished as previously described (20). The immunoperoxidase color reaction was developed by incubation with diaminobenzidine (DAB). A positive control, consisting of nasal polyp tissue, and a negative control without primary antibody were included in each staining run.

Image Analysis

Small airways (< 3 mm diameter) within a section were identified with the epithelial marker CAM 5.2. The number of cells positive for the appropriate cell marker in a consecutive section in an area of submucosa 50 μm deep to the basement membrane was counted by a blinded investigator. The area was measured with an image analyzer (Colour FreeLance software; Sight Systems, Hove, UK), and all cell counts were expressed as cells/mm2.

Statistical Analysis

Statistical analyses of the data were done with the Mann–Whitney U test. Results are expressed as median (range). Bonferroni's correction was applied if more than one comparison was made between groups.

Smoking versus Nonsmoking Groups

The number of MBP-positive cells (total eosinophils) infiltrating the small-airway submucosa was increased in the smoking group (49.2 [range: 6.4 to 217] cells/mm2, n = 20) as compared with the nonsmoking group (13.8 [range: 0 to 100] cells/mm2, n = 19) (p = 0.001) (Figure 1a). In addition, we detected an increase in the number of ECP-positive cells (activated eosinophils) infiltrating the small-airway submucosa in the smokers (25.4 [range: 0 to 111] cells/mm2, n = 20) as compared with the nonsmokers (3.8 [range: 0 to 205] cells/mm2, n = 21) (p = 0.010) (Figure 1b).

There was no difference in the number of NE-positive cells (neutrophils) infiltrating the small airway submucosa in smokers (20.1 [range: 3.1 to 78.8] cells/mm2, n = 21) and nonsmokers (12.0 [range: 2 to 36.3] cells/mm2, n = 22) (Figure 2a). There was, however, a significant increase in NE-positive cells when the smoking group (20.1 [range: 3.1 to 78.8] cells/mm2, n = 21) was compared with the group of lifelong nonsmokers (10.3 [range: 3 to 12.2] cells/mm2, n = 5) (p = 0.019) (Figure 2b).

There was no difference in the number of CD3+ cells (total T cells) infiltrating the small-airway submucosa in the smoking (504 [range: 223 to 2,218] cells/mm2, n = 21) and nonsmoking groups (615 [range: 260 to 1,375] cells/mm2, n = 22). Furthermore, no significant differences were observed in the number of CD25+ cells (representing activated T lymphocytes) infiltrating the small-airway submucosa in the smoking (6 [range: 0 to 65.0] cells/mm2, n = 22) and nonsmoking groups (7.1 [range: 0 to 84.0] cells/mm2, n = 22).

Although there was a trend toward an increase in CD8+ cells in smokers (200 [range: 70 to 959] cells/mm2, n = 21) as compared with nonsmokers (152 [range: 42 to 522] cells/mm2, n = 22) (p = 0.08), this did not achieve statistical significance. Similarly, there was a nonsignificant trend toward a decrease in the number of CD4+ cells in the smokers (198.5 [range: 22 to 689] cells/mm2, n = 22) as compared with the nonsmokers (253 [range: 48 to 577] cells/mm2, n = 22) (p = 0.068).

When the proportion of infiltrating CD8+ cells as a fraction of total (CD3+) T cells was calculated, we detected a significant increase in the CD8+/CD3+ ratio in smokers (0.46 [range: 0.17 to 0.91], n = 21) as compared with nonsmokers (0.29 [range: 0.07 to 0.61], n = 22) (p = 0.003) (Figure 3a). In addition, there was a significant decrease in the CD4+/CD8+ cell ratio in the smokers (0.88 [range: 0.08 to 2.7], n = 21) as compared with the nonsmokers (1.5 [range: 0.48 to 3.8], n = 22 (p = 0.005) (Figure 3b).

The CD8+/CD3+ cell ratio was related to the number of pack-years smoked when data from all subjects were analyzed (p = 0.016, r = 0.36, n = 43) (Figure 4a), and was inversely related to the duration of cessation of smoking when data for smokers and ex-smokers were analyzed (p = 0.003, r = −0.47, n = 38) (Figure 4b). Furthermore, there was a highly significant correlation between the CD8+/CD3+ cell ratio and the number of both MBP-positive cells (p = 0.007, r = 0.43, n = 39) (Figure 5a) and number of NE-positive cells (p = 0.004, r = 0.44, n = 42) (Figure 5b).

The number of NE-positive cells was significantly related to the number of MBP-positive cells (p = 0.0003, r = 0.58, n = 38) (Figure 5c). There was also a significant correlation between the number of CD25+ cells and both the number of NE-positive cells (p = 0.020, r = 0.35, n = 42) and number of MBP-positive cells (p = 0.025, r = 0.36, n = 38).

There was no difference in the CD68+ cell numbers infiltrating the small-airway submucosa of smokers (67 [range: 43 to 109] cells/mm2, n = 20) and nonsmokers (66 [range: 35 to 121] cells/mm2, n = 20).

Obstructed Airflow versus Nonobstructed Airflow Groups

No differences were found between groups with and without airflow obstruction in the number of cells infiltrating the small-airway submucosa that were positive for CD3, CD4, CD8, MBP, ECP, NE, or CD68. Furthermore, we were unable to detect any difference between groups with and without airflow obstruction in the CD4+/CD8+ cell ratio or the CD8+/ CD3+ cell ratio among cells infiltrating the small-airway submucosa (Table 2).

Table 2. NUMBER OF CELLS INFILTRATING THE SMALL AIRWAYS STAINING POSITIVE  FOR EACH CELL MARKER IN GROUPS WITH AND WITHOUT AIRFLOW OBSTRUCTION EXPRESSED AS MEDIAN (RANGE)

Nonobstructed AirflowObstructed Airflow
MBP-positive  20.5 (0–88.6) (n = 18) 40.9 (0.9–217) (n = 16)
ECP-positive      11.8 (0–97) (n = 19)    4.1 (0–205) (n = 17)
NE-positive  18.5 (2–78.8) (n = 20) 23.8 (3.1–43.7) (n = 18)
CD3+ 591 (243–1,335) (n = 20)508 (223–2,218) (n = 19)
CD4+    235 (116–391) (n = 20)  200 (22–689) (n = 19)
CD8+   182 (70–694) (n = 19)  172 (42–959) (n = 19)
CD68+   66 (41–121) (n = 19) 66.5 (35.0–109) (n = 16)
CD25+    7.7 (0–42.5) (n = 19)   7.6 (0–84) (n = 19)
CD4+/CD8+  1.07 (0.35–3.7) (n = 19)1.14 (0.08–3.39) (n = 19)
CD8+/CD3+ 0.38 (0.08–0.83) (n = 19)0.43 (0.07–0.91) (n = 19)

The majority of cases of COPD are caused by cigarette smoking, but only 20% of smokers go on to develop clinically significant COPD (1, 2). This has led to interest in the changes in inflammatory cell populations induced by smoking, and the relationship between these changes and the development of obstruction. The obstruction in COPD is thought to be due to increased resistance at the level of the small airways, but obtaining in vivo samples at this site is difficult (7). To date, most studies have examined the large airways through bronchoscopic bronchial biopsy or the small airways indirectly, through BAL (4, 11-16, 18, 19). In this study we used immunohistochemistry with sensitive and specific monoclonal antibodies applied to frozen sections from randomly selected blocks of peripheral lung obtained at surgery for peripheral lung masses. All tumor masses were peripheral and nonobstructing, and in order to avoid influence from the presence of tumor, sections were taken from sites both macroscopically and microscopically free of tumor. We demonstrated that smokers have an abnormal cellular infiltrate into the small-airway submucosa. This infiltrate consists of an increase in total and activated eosinophils and in neutrophils, and an increase in the CD8+/CD3+ cell ratio. These changes were independent of the presence or absence of airflow obstruction. Furthermore, the increased CD8+/CD3+ cell ratio showed a dose relationship to pack-years smoked and an inverse time relationship to months since smoking cessation, reinforcing the association between cigarette smoking and increased CD8+/CD3+ cell ratio. Moreover, the CD8+/CD3+ ratio was related to the number of infiltrating eosinophils and neutrophils, suggesting that CD8+ cells may contribute to the population of these cells in the small-airway submucosa in smokers.

The present study is the first to demonstrate an increase in total eosinophils in the small-airway submucosa of smokers as compared with nonsmokers. The presence of increased numbers of ECP-positive cells suggests that the eosinophils in the submucosa are activated. No difference in eosinophil infiltration was observed in groups with and those without airflow obstruction, suggesting that eosinophilia may be related to smoking per se. These results complement those of Lacoste and colleagues, who demonstrated an increase in large-airway submucosal eosinophils in smokers (15).

In addition, we demonstrated an increase in small-airway neutrophils in smokers as compared with lifelong nonsmokers. No difference was noted in the groups with and that without airflow obstruction, suggesting that the progression to obstruction may depend upon host factors, such as subtle differences in antiprotease or antioxidant status, involved in defense against neutrophil-mediated damage.

We were unable to detect a difference in total (CD3+) T cells or macrophages (CD68+) in the small-airway submucosa of nonsmokers and that of smokers, or in subjects with and those without airflow obstruction. This contrasts with the finding in previous studies of the large-airway submucosa of an increase in total T cells and macrophages (12, 14, 16) in subjects with chronic bronchitis, and suggests that smoking has differential effects on the inflammatory infiltrate in the small and large airways. We could detect no difference between smokers and nonsmokers in the numbers of activated (CD25+) T cells infiltrating the small-airway submucosa.

The small-airway submucosal inflammatory infiltrate did not differ between groups with and without obstruction. This suggests that differences in host defenses, such as the ability to respond to oxidant or proteolytic burden, may be important in determining the outcome of the inflammatory infiltrate in smokers who go on to develop airflow obstruction. Alternatively, the small-airway submucosa may not have been the major site responsible for airflow obstruction in our group of patients.

We found an increase in the CD8+/CD3+ cell ratio among cells infiltrating the small-airway submucosa of smokers. This novel finding is consistent with data showing an increase in CD8+ cells in peripheral blood and BALF of smokers, and in the large-airway submucosa of smokers with COPD (3, 4, 16). The importance of the CD8+/CD3+ cell ratio is underscored by its dose and time relationship to pack-years smoked and months since smoking cessation. Furthermore, the CD8+/ CD3+ cell ratio also correlated with the number of eosinophils and neutrophils infiltrating the small-airway submucosa, and the number of infiltrating eosinophils correlated with the number of infiltrating neutrophils, suggesting that similar mechanisms may be responsible for their recruitment. CD8+ cells are capable of switching to interleukin-5 (IL-5) production, a well-described eosinophil chemotactic and activation cytokine (21). CD8+ cells are also known to produce IL-8, which is a powerful chemoattractant for neutrophils (22). CD8+ cells may therefore play a central role in coordinating the influx of eosinophils and neutrophils in smoking-induced small-airway inflammation, analogously to the role of CD4+ cells in asthma. A recent study has demonstrated genetic control of the ratio between CD8+ and CD4+ cells, with a small (5%) percentage of the study population having a CD4+/CD8+ ratio of < 1 (23). O'Shaughnessy and coworkers have suggested that individuals with a genetically determined increase in their CD8+ cell population may be more susceptible to a further increase in CD8+ cells induced by smoking, and that this might explain why only a proportion of smokers proceed to develop COPD (16).

In conclusion, the present study highlights the central role of CD8+ cells in small-airway inflammation induced by smoking. An increased CD8+/CD3+ cell ratio correlated in a dose- and time-dependent manner with cigarette exposure. Furthermore, CD8+ cells are capable of generating potent chemoattractants, which may explain the increase in neutrophils and eosinophils seen in the smoking subjects in our study. These inflammatory changes in the small-airway submucosa are independent of the presence of airflow obstruction, suggesting that cofactors, either genetic or environmental, are important in the development of such obstruction, or that the site mainly responsible for airway limitation is elsewhere.

Supported by a grant from Boehringer Ingelheim, GmbH.

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Correspondence and requests for reprints should be addressed to Prof. T. H. Lee, Department of Allergy and Respiratory Medicine, 5th Floor, Thomas Guy House, Guy's Hospital, London SE1 9RT, UK.

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