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(Chest. 2001;120:602-607.)
© 2001 American College of Chest Physicians

High Concentrations of ß-Chemokines in BAL Fluid of Patients With Diffuse Panbronchiolitis*

Jun-ichi Kadota, MD{dagger}; Hiroshi Mukae, MD; Kazunori Tomono, MD and Shigeru Kohno, MD, FCCP

* From the Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan. {dagger} Currently at Oita Medical University.

Correspondence to: Jun-ichi Kadota, MD, Second Department of Internal Medicine, Oita Medical University, 1-1 Hasama-machi, Oita 879-5593, Japan; e-mail: kadota{at}oita-med.ac.jp


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: T cells are important cellular components of bronchial inflammation in diffuse panbronchiolitis (DPB). ß-Chemokines such as RANTES (regulated on activation, normal T-cell expressed and secreted) and macrophage inflammatory peptide (MIP)-1{alpha} are closely related to the migration of inflammatory cells into the lung. In this study, we investigate the contribution of ß-chemokines to the accumulation of T cells in the lungs of patients with DPB.

Patients and methods: We determined the levels of ß-chemokines in BAL fluid (BALF) and the correlation between these levels and T-cell subsets in BALF of 23 patients with DPB and 16 healthy subjects by sandwich enzyme-linked immunosorbent assay and flow cytometry.

Results: Percentages of CD3+ human leukocyte antigen (HLA)-DR+, CD8+, and CD8+HLA-DR+ cells in BALF of patients were significantly higher than in the control BALF. The absolute number of CD8+HLA-DR+ cells was also higher in BALF of patients than in the control BALF (p < 0.0001). Phenotypic analysis of CD4+ cells in BALF showed a similar percentage of CD4+CD45RA+ cells and CD4+CD29+ cells in patients and normal subjects. The concentrations of RANTES and MIP-1{alpha} in BALF of patients with DPB were significantly higher than in BALF of normal subjects (p < 0.05). In addition, there was a significant correlation between the absolute number or percentage of CD8+HLA-DR+ cells and MIP-1{alpha} concentration in BALF.

Conclusions: Our results suggest that the interaction between activated CD8+ T cells and MIP-1{alpha} may contribute to the pathogenesis of DPB.

Key Words: BAL • ß-chemokines • CD8+ T cells • diffuse panbronchiolitis


   Introduction
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 Introduction
Materials and Methods
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Diffuse panbronchiolitis (DPB) is a disease entity first described by Homma and coworkers.1 The disease is characterized by chronic inflammation of the respiratory bronchioles and infiltration of inflammatory cells.1 The clinical features of DPB are those of chronic sinopulmonary infection and inflammation. Previous reports2 3 4 have shown the presence of numerous neutrophils in the BAL fluid (BALF) of DPB patients associated with high concentrations of interleukin-8 in BALF, suggesting that accumulation of neutrophils and interleukin-8 secretion in the airway lumen may play an important role in the pathogenesis of the disease. In contrast, the histologic pattern in DPB is characterized by thickening of the walls of respiratory bronchioles, with infiltration of lymphocytes, plasma cells, and histiocytes.1 In addition, hyperplasia of the bronchus-associated lymphoid tissue is usually observed more frequently in DPB than in other respiratory diseases.5 Furthermore, we6 7 have demonstrated a marked increase in CD4+ human leukocyte antigen (HLA)-DR+ cells, especially memory T cells with a dominant increase of CD8+ HLA-DR+ cells, especially cytotoxic T cells in BALF of DPB patients compared with healthy subjects. These observations suggest that in addition to neutrophils, T cells are also important cellular components of bronchial inflammation in patients with DPB.

ß-Chemokines such as RANTES (regulated on activation, normal T-cell expressed and secreted) and macrophage inflammatory peptide (MIP)-1{alpha} are closely related to the expression of adhesion molecules and the migration of inflammatory cells into the lung. RANTES is primarily a T-cell product and a selective chemotactic factor for memory T cells,8 9 and reports have indicated that MIP-1{alpha} attracts T cells,10 especially CD8+ cells.11

In the present study, to evaluate the contribution of ß-chemokines to the accumulation of T cells in the lungs of patients with DPB, we determined the levels of ß-chemokines in BALF of DPB and correlated these levels with lymphocytosis and T-cell subsets in BALF.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
We examined 16 normal control subjects (12 men and 4 women; mean age, 26 years; age range, 19 to 33 years; 15 nonsmokers) and 23 patients with DPB (13 men and 10 women; mean age, 52 years; age range, 16 to 70 years; 17 nonsmokersand 5 ex-smokers) who fulfilled all clinical criteria for DPB published by the Japanese Ministry of Health and Welfare (n = 16) or histopathologically by surgical lung biopsy (n = 7) as shown in Table 1 . The clinical criteria of DPB were as follows: (1) symptoms (chronic cough, sputum, and dyspnea on exertion); (2) physical signs (coarse crackles, rhonchi, or wheezes on chest auscultation); (3) chest radiographs (bilateral fine nodular shadows, mainly in the lower lung fields often with hyperinflation of the lungs); chest CTs are more helpful in the diagnosis showing small round areas of high attenuation with a centrilobular distribution, branching linear areas of high attenuation, and hypoattenuation in the peripheral lung; (4) pulmonary function tests and blood gas analysis (FEV1 percent predicted of < 70% and PaO2 < 80 mm Hg); (5) elevated titers of cold hemagglutinin (x 64 or higher); and (7) history or coexistence of chronic parasinusitis. All patients complained of productive cough for > 2 years prior to presentation. The median values (range) of FEV1 percent predicted, PaO2, and cold hemagglutinin titer in the patients were 68.2% (41.8 to 96.7%), 70.9 mm Hg (59.8 to 88.8 mm Hg), and x 128 (x 8 to x 1,024), respectively (Table 1) .


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  		Table 1. Clinical Characteristics of 23 Patients With DPB *

 
BAL was performed in all patients and normal subjects. Patients who had physical or radiologic signs suggestive of pneumonia or acute exacerbation of their disease before enrollment in the study were administered adequate antibiotic therapy. Accordingly, none had pulmonary infection within 1 month prior to BAL, and BALF culture findings were negative for bacteria in all patients. The design of the study was approved by our institutional review board and was fully explained, and a signed consent was obtained from each patient.

BAL and Cell Preparation
BAL was performed using a standard technique. Instillation of 50 mL of saline solution was performed four times. The lavage fluid was passed through two sheets of gauze and centrifuged at 500g for 10 min at 4°C, and the supernatant was stored at - 80°C until use. After washing twice with phosphate-buffered saline solution (PBS), cells were suspended with 10% heat-inactivated fetal calf serum and counted using a hemocytometer. An aliquot was then adjusted to 2 x 105/mL, and 0.2-mL sample of each cell suspension was spun down onto a glass slide at 160g for 2 min using a cytocentrifuge (Cytospin 2; Shandon Instruments; Sewickley, PA). The slides were later dried, fixed, and then stained by the May-Giemsa method. Two hundred cells were identified under a photomicroscope. The remaining cells were resuspended in PBS, supplemented with 10% fetal calf serum and incubated in plastic flasks for 90 min at 37°C in humidified 5% CO2-air for depletion of alveolar macrophages. The cells were then centrifuged at 500g for 5 min at 4°C, the supernatant was discarded, and the cells were resuspended in PBS. The cells were washed twice in PBS and passed through 100-µm nylon mesh, finally adjusted to a concentration of 1 x 106/mL. Viable cells constituted > 90% of nonadherent cells, which were collected for flow cytometric analysis using the trypan blue exclusion test.

Monoclonal Antibody
The following monoclonal antibodies were used in our study: phycoerythrin-conjugated anti-CD3, CD4, and CD8 (Becton Dickinson; Mountain View, CA); and fluorescein isothyanate (FITC)-conjugated anti-human lymphocyte antigen (HLA)-DR, and anti-CD45RA and CD29 antibodies (Coulter Immunology; Hialeah, FL). Mouse IgG1 conjugated with FITC or phycoerythrin (Becton Dickinson) was used to determine the borderline between stained and unstained cells in flow cytometric analysis.

Two-Color Direct Immunofluorescence Staining
The concentration of BALF cells was adjusted to 1 x 106/mL. A total of 5 µL of each monoclonal antibody was placed into a 12 x 15-mm polystyrene tube (Falcon Plastics; Oxnard, CA) and 100 µL of the cell suspension (1 x 105 cells) was added. The cells were incubated for 30 min on ice in the dark, washed once in cold PBS containing 0.1% sodium azide, and then resuspended in cold PBS containing 0.5% paraformaldehyde. The fixed cells were kept in darkness at 4°C until analysis.

Two-Color Flow Cytometry
Stained cells were analyzed on a flow cytometer equipped with an argon-ion laser and set at 488 nm (FACScan; Becton Dickinson, FACS Division), and a computer system (Consort 30; Becton Dickinson) was used for data acquisition and analysis. A minimum of 10,000 events were collected for each sample. A cell gate containing lymphocytes was established on the basis of forward and side light scatter. To determine the borderline between stained and unstained cells, the cells were also stained with mouse IgG1-conjugated FITC or phycoerythrin. The percentages were calculated based on the number of lymphocytes found in each quadrant. Interassay reproducibility was checked using beads (CaliBRITE; Becton Dickinson) and a software program (AutoCOMP; Becton Dickinson).

Measurement of RANTES and MIP-1{alpha}
Samples of BALF supernatant were concentrated by Centriprep-3 (Amicon a GRACE Company; Beverly, MA), which is used to concentrate low-molecular-weight components. The cutoff value for molecular weight is 3,000 d. In this concentration procedure, the recovery of each ß-family chemokine was > 90%, and the magnification of concentration was calculated by the ratio of protein consistency in nonconcentrated BALF supernatant to concentrated BALF supernatant, which was measured using assay (DC Protein Assay; Bio-Rad Laboratories; Hercules, CA), and the original level of chemokines was corrected by this ratio. The level of RANTES and MIP-1{alpha} was quantified using enzyme-linked immunosorbent assay kits (Quantikine; R&D systems, Minneapolis, MN). Since BAL procedure has a dilutional effect on the recovery of cytokines, measurements are occasionally standardized to albumin or urea. Preliminary analysis showed a good correlation between the nonstandardized and standardized values by albumin concentration in BALF (r = 0.685, p < 0.01 for RANTES; r = 0.613, p < 0.05 for MIP-1{alpha}). Thus, the reported levels of chemokines are those of the measured concentrations rather than those relative to albumin concentration. The detection limits were 2.5 pg/mL and 2.0 pg/mL for RANTES and MIP-1{alpha}, respectively. Cross reactions with other cytokines were not observed.

Statistical Analysis
All values were expressed as median (range). The Mann-Whitney U test was used to examine differences between unpaired samples. We also used the Spearman’s rank correlation to examine the relationship between lymphocyte subsets and ß-chemokines. Statistical analysis was performed using software (Statview-J 4.5; Abacus Concepts; Berkeley, CA). A p value of < 0.05 was considered significant.


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Differential Cell Count of BALF
Table 2 shows the characteristics of BALF in patients with DPB and normal subjects. The recovered volume of BALF in patients with DPB was less than that in normal subjects. However, in the former group, cell counts, percentage of neutrophils, and number of lymphocytes were significantly higher, while the percentage of macrophages was significantly lower, relative to the control. The absolute number of alveolar macrophages in patients with DPB was not different from the normal subjects (data not shown).


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  		Table 2. Total and Differential Cell Counts in BALF *

 
Lymphocyte Subsets in BALF
The percentages of CD3+, CD4+, and CD4+HLA-DR+ cells were similar in patients and normal subjects, while those of CD3+HLA-DR+, CD8+, and CD8+HLA-DR+ cells in BALF of patients with DPB were significantly higher than normal subjects (Table 3 ). The absolute number of CD8+HLA-DR+ cells was also higher in patients than in control subjects: 0.20 x 105/mL (range, 0.02 to 0.89 x 105/mL) vs 0.01 x 105/mL (range, 0.001 to 0.07 x 105/mL; p < 0.0001). The CD4/CD8 ratio was lower in patients than in normal subjects, albeit statistically insignificant. Phenotypic analysis of CD4+ cells in BALF showed a similar percentage of CD4+CD45RA+ cells as naive T cells and CD4+CD29+ cells as memory T cells in patients and normal subjects.


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  		Table 3. Proportion of T-Cell Subsets in BALF*

 
RANTES and MIP-1{alpha} Concentrations in BALF
Figure 1 shows the concentrations of ß-chemokines in BALF obtained from patients with DPB and normal subjects. RANTES (9.5 pg/mL; range, 0.2 to 54.3 pg/mL) and MIP-1{alpha} (8.1 pg/mL; range, 1.9 to 39.8 pg/mL) concentrations in patients with DPB were significantly higher than in normal subjects: 1.2 pg/mL (range, 0.0 to 12.7 pg/mL) and 1.9 pg/mL (range, 0.2 to 5.8 pg/mL), respectively (p < 0.05).



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  		Figure 1. Concentrations of RANTES (left) and MIP-1{alpha} (right) in BALF of normal subjects and patients with DPB. The lower and upper borders of the whisker box plot represent the 25th to 75th percentiles, while the bar across the box represents the median values, and the whiskers on each box represent the 10th to 90th percentiles (p < 0.05, Mann-Whitney U test).

 
Correlation Between MIP-1{alpha} Concentration and CD8+HLA-DR+ Cells in BALF
Since ß-chemokines are chemotactic factors for T cells,8 9 11 we examined the association in the paired samples between ß-chemokines and BALF cells obtained from 11 patients with DPB. There was a significant correlation between the absolute number or percentage of CD8+HLA-DR+ cells and MIP-1{alpha} concentration in BALF (r = 0.439, p < 0.005; r = 0.565, p < 0.0001, respectively; Fig 2 ). No significant correlations were observed between RANTES concentration and the percentage or absolute number of CD4+CD29+ memory T cells in BALF (r = 0.205 or r = 0.37, respectively). There were no significant correlations between MIP-1{alpha} or RANTES concentration and other lymphocyte subsets in BALF (data not shown).



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  		Figure 2. Correlation between the absolute number (left) or percentage (right) of CD8+ HLA-DR+ cells and the concentration of MIP-1{alpha} in the paired BALF of 11 patients with DPB.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present study demonstrated a higher percentage and number of CD8 cells carried HLA-DR antigen and high concentrations of MIP-1{alpha} in the lung of patients with DPB. Furthermore, there was a significant correlation between those cells and the chemokine. Our study confirmed our earlier findings6 7 that CD8 cells that carry HLA-DR antigen, representing activated CD8 T cells, are an important cellular component in the pathogenesis of DPB, and similar findings12 13 showing predominance of CD8+ over CD4+ cells in the lamina propria just below the epithelial basement membrane in patients with bronchiectasis and chronic bronchitis.

MIP-1{alpha} is involved in a wide variety of biological activities, such as activation of monocytes or basophils and chemotaxis of macrophages and neutrophils.14 Denis11 described it as chemoattractant for CD8+ T cells in the lung of hypersensitivity pneumonitis, and our studies15 demonstrated that the interaction between activated T cells bearing CD25 and MIP-1{alpha} may contribute to pulmonary involvement in human T-lymphotropic virus type-1 carriers. In contrast, the levels of MIP-1{alpha} in BALF of patients with sarcoidosis, representative of CD4+ T-cell dominant disease were not elevated in our previous study.16 These findings indicate that MIP-1{alpha} may be closely related to the migration of T cells, especially CD8+ T cells into the lung of CD8+ T-cell dominant disease. In this context, BALF concentrations of MIP-1{alpha} correlated significantly with the number of CD8+HLA-DR+ cells in our study, suggesting that MIP-1{alpha} may play an important role in the pathogenesis of DPB through the recruitment or activation of CD8+ T cells.

RANTES is primarily a T-cell product and selectively attracts memory T cells in vitro.9 We have previously demonstrated16 the presence of high concentrations of RANTES in BALF of patients with sarcoidosis. In addition, there was a significant correlation between RANTES concentrations and the percentage or number of CD4+ CD29+ cells. Moreover, the mean concentration of RANTES was similar to that reported17 to induce T-cell binding to endothelial cells. The present study has also provided the evidence that RANTES concentrations are increased in BALF of patients with DPB. However, there was no correlation between these concentrations and the percentage or number of CD4+ CD29+ memory T cells in contrast to sarcoidosis, although RANTES concentrations in patients with DPB were quite similar to concentrations in patients with sarcoidosis. Furthermore, the percentage of CD4+ CD29+ memory T cells in BALF of DPB patients did not differ from that in normal subjects. Considered together, we suggest that RANTES is probably not directly involved in the pathogenesis of DPB, but rather involved in sarcoidosis.

In conclusion, we have demonstrated the presence of high density of activated CD8+ T cells and high MIP-1{alpha} concentrations in the lungs of patients with chronic airway disease, DPB. Our results suggest that the interaction between these inflammatory cells and MIP-1{alpha}, rather than RANTES, may contribute to the pathogenesis of DPB. Because we could not define the direct effect of MIP-1{alpha} on T cells in BALF of these patients, further studies are required to define the role of activated CD8+ T cells and MIP-1{alpha} in DPB.


   Acknowledgements
 
The authors thank Atsushi Yokoyama for the technical support, and also Dr. F. G. Issa (Word-Medex; Sydney, Australia) for reading and editing the article.


   Footnotes
 
Abbreviations: BALF = BAL fluid; DPB = diffuse panbronchiolitis; FITC = fluorescein isothyanate; HLA = human leukocyte antigen; MIP = macrophage inflammatory peptide; PBS = phosphate-buffered saline solution; RANTES = regulated on activation, normal T-cell expressed and secreted

Received for publication November 16, 2000. Accepted for publication February 21, 2001.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Homma, H, Yamanaka, A, Tanimoto, S, et al (1983) Diffuse panbronchiolitis: a disease of the transitional zone of the lung. Chest 83,63-69[Abstract/Free Full Text]
  2. Kadota, J, Sakito, O, Kohno, S, et al (1993) A mechanism of erythromycin treatment in patients with diffuse panbronchiolitis. Am Rev Respir Dis 147,153-159[ISI][Medline]
  3. Sakito, O, Kadota, J, Kohno, S, et al (1996) Interleukin 1ß, tumor necrosis factor-{alpha}, and interleukin 8 in bronchoalveolar lavage fluid of patients with diffuse panbronchiolitis: a potential mechanism of macrolide therapy. Respiration 63,42-48[ISI][Medline]
  4. Oishi, K, Sonoda, F, Kobayashi, S, et al (1994) Role of interleukin-8 (IL-8) and an inhibitory effect of erythromycin on IL-8 release in the airways of patients with chronic airway diseases. Infect Immun 62,4145-4152[Abstract/Free Full Text]
  5. Sato, A, Chida, K, Iwata, M, et al (1992) Study of bronchus-associated lymphoid tissue in patients with diffuse panbronchiolitis. Am Rev Respir Dis 146,473-478[ISI][Medline]
  6. Mukae, H, Kadota, J, Kohno, S, et al (1995) Increase in activated CD8+ cells in bronchoalveolar lavage fluid in patients with diffuse panbronchiolitis. Am J Respir Crit Care Med 152,613-618[Abstract]
  7. Kawakami, K, Kadota, J, Iida, K, et al (1997) Phenotypic characterization of T cells in bronchoalveolar lavage fluid (BALF) and peripheral blood of patients with diffuse panbronchiolitis; the importance of cytotoxic T cells. Clin Exp Immunol 107,410-416[CrossRef][ISI][Medline]
  8. Schall, TJ, Jongstra, J, Dyer, BJ, et al (1988) A human T cell-specific molecule is a member of a new gene family. J Immunol 141,1018-1025[Abstract]
  9. Conlon, K, Lloid, A, Chattopadhyay, U, et al (1995) CD8+ and CD45RA+ human peripheral blood lymphocytes are potent sources of macrophage inflammatory protein 1, interleukin-8 and RANTES. Eur J Immunol 25,751-756[ISI][Medline]
  10. Zipfel, PF, Balke, J, Irving, SG, et al (1989) Mitogenic activation of human T cells induces two closely related genes which share structural similarities with a new family of secreted factors. J Immunol 142,1582-1590[Abstract]
  11. Denis, M (1995) Proinflammatory cytokines in hypersensitivity pneumonitis. Am J Respir Crit Care Med 151,164-169[Abstract]
  12. Silvia, LE, Jr, Jones, JAH, Cole, PJ, et al (1989) The immunological component of the cellular inflammatory infiltrate in bronchiectasis. Thorax 44,668-673[Abstract]
  13. Fournier, M, Lebargy, F, Ladurie, FLR, et al (1989) Intraepithelial T-lymphocyte subsets in the airways of normal subjects and of patients with chronic bronchitis. Am Rev Respir Dis 140,737-742[ISI][Medline]
  14. Koch, AE, Kunkel, SL, Harlow, LA, et al (1994) Macrophage inflammatory protein-1{alpha}: a novel chemotactic cytokine for macrophages in rheumatoid arthritis. J Clin Invest 93,921-928
  15. Seki, M, Kadota, J, Higashiyama, Y, et al (1999) Elevated levels of ß-chemokines in bronchoalveolar lavage fluid (BALF) of individuals infected with human T lymphotropic virus type-1 (HTLV-1). Clin Exp Immunol 118,417-422[CrossRef][ISI][Medline]
  16. Iida, K, Kadota, J, Kawakami, K, et al (1997) Analysis of T cell subsets and ß-chemokines in patients with pulmonary sarcoidosis. Thorax 52,431-437[Abstract]
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