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. 2001 Dec;126(3):545–550. doi: 10.1046/j.1365-2249.2001.01699.x

Characterization of CD44 expressed on alveolar macrophages in patients with diffuse panbronchiolitis

S Katoh *, Y Matsubara *, H Taniguchi *, K Fukushima †, H Mukae *, J Kadota *, S Matsukura *, S Kohno *
PMCID: PMC1906232  PMID: 11737075

Abstract

Interleukin (IL)-8 may play an important role in neutrophil infiltration in the airways of patients with diffuse panbronchiolitis (DPB). Furthermore, alveolar macrophages could produce IL-8 subsequent to CD44-hyaluronic acid (HA) interaction. The purpose of this study was to evaluate the contribution of CD44 expressed on alveolar macrophages to the pathogenesis of DPB. We examined the concentration of soluble CD44 (sCD44) in bronchoalveolar lavage fluid (BALF) and CD44 expression on macrophages in BALF from patients with DPB before and after low-dose, long-term macrolide therapy. We also assessed the HA-binding ability of alveolar macrophages as a functional analysis of the CD44 molecule. The sCD44 concentration in BALF was significantly lower in patients with DPB than in healthy volunteers. Percentages of alveolar macrophages expressing low CD44 (CD44 low+) and HA-nonbinding alveolar macrophages were higher in patients with DPB compared with healthy volunteers. Furthermore, macrolide therapy normalized CD44 expression and HA-binding ability of macrophages in BALF from DPB patients. Our findings suggest that alveolar macrophage dysfunction could result from abnormalities of CD44 expression in patients with DPB and that these events could contribute to the pathogenesis of DPB.

Keywords: diffuse panbronchiolitis (DPB), CD44, hyaluronic acid (HA), bronchoalveolar lavage fluid (BALF), alveolar macrophage

Introduction

Diffuse panbronchiolitis (DPB) is a clinicopathological disease entity characterized by chronic inflammation of the respiratory bronchioles with infiltration of inflammatory cells, such as lymphocytes and plasma cells [1]. A marked increase in neutrophil infiltration also characterizes airway inflammation in patients with DPB [2,3]. Interleukin (IL)-8 is a major neutrophil chemotactic factor in the lung and can be produced by monocytes, macrophages and, to a lesser extent, by lymphocytes, fibroblasts and endothelial cells [4,5]. We have recently reported a significant correlation between increased neutrophil numbers and levels of IL-8 in bronchoalveolar lavage fluid (BALF) obtained from patients with DPB. Neutrophils induced by IL-8 may play an important role in the pathogenesis of DPB [3,6].

Treatment with low-dose, long-term erythromycin has been established as an effective therapy for DPB [7–9]. Long-term treatment with clarithromycin or roxithromycin, two 14-membered macrolide antibiotics derived from erythromycin, is also effective against DPB [10,11]. We have previously reported that treatment with erythromycin and roxithromycin reduces the number of neutrophils and levels of IL-8 in BALF of patients with DPB [6,11].

CD44 is a cell adhesion molecule thought to be involved in several physiologic and pathologic processes such as haemopoiesis, homing to mucosal lymphatic tissue, and lymphocyte infiltration into inflammatory tissues [12–15]. CD44 also functions as a receptor for hyaluronic acid (HA) [16,17]. Although most blood cells express CD44, few use it to recognize HA [18]. Lymphocytes can be induced to bind HA upon activation [19,20]. It has been reported that human alveolar macrophages, but not freshly isolated peripheral blood monocytes, can bind HA [21].

CD44 can be used as a signal transducing receptor. Interestingly, monocytic lineage cells such as alveolar macrophages can be induced to produce IL-8 by CD44–HA interaction [22]. We hypothesized that surface CD44 on alveolar macrophages could play an important role in the airway inflammation caused by neutrophils in patients with DPB. In the present study, we demonstrated low levels of soluble CD44 (sCD44) in BALF of patients with DPB. We then focused on the expression and HA-binding ability of CD44 on alveolar macrophages in patients with DPB. Expression levels of CD44 on macrophages and percentages of HA-binding macrophages in BALF were compared before and after long-term macrolide therapy in patients with DPB.

Materials and methods

Patient population

Included in this study were 19 untreated patients with DPB (nine males and 10 females, aged 48·9 ± 4·4 years), and 14 healthy volunteers (11 males and three females, aged 26·4 ± 1·2 years). Healthy volunteers had no previous history of pulmonary disease. None of the patients in this study had been previously treated with corticosteroids. Three patients with DPB and two of the volunteers were smokers. The diagnosis of DPB was based on the clinical criteria established by Japanese Ministry of Health and Welfare. These included: (1) symptoms of chronic cough, sputum, and dyspnoea on exertion; (2) physical signs with rales; (3) diffuse disseminated fine nodular shadows, mainly in the lower lung fields, with hyperinflation of the lungs on chest roentgenogram or computed tomography; (4) pulmonary function tests and blood gas analysis; FEV1% < 70% and PaO2 < 80 mmHg; (5) elevated titres of cold haemagglutinin: > × 64, and (6) complicating or past history of chronic sinusitis. BAL was performed in all patients and healthy volunteers. Since a low-dose and long-term macrolide antibiotic regimen has been established as an effective therapy for DPB [9], all patients were treated with oral macrolide antibiotics. None received other antibiotics or corticosteroids during the course of the study. In addition, a second BAL was performed in 16 patients after improvement in at least two of criteria (1)–(3) and one of criteria (4) listed above. Erythromycin, roxithromycin or clarithromycin was administered to four patients at 600 mg/day for 17·8 ± 10·2 months, to three patients at 150 mg/day for 11·7 ± 5·7 months and to 10 patients at 200 mg/day for 6·6 ± 0·4 months.

Bronchoalveolar lavage (BAL)

After obtaining informed consent, BAL was performed using a flexible fibreoptic bronchoscope (Olympus BF-P20) under local anaesthesia of the upper airway with 4% lidocaine, as described previously [23]. Briefly, the bronchoscope was wedged into the subsegmental bronchus of the right middle lobe, and 150 or 200 ml normal saline was instilled in 50 ml aliquots. Harvested BALF was filtered through sterile nylon mesh and centrifuged (Shandon Cytospin II) at 160 × g for 2 min to obtain the cell preparation. The cells were later stained using the May-Giemsa method and a differential count was performed on 200 cells. The remaining fluid was centrifuged at 500 × g for 5 min and the supernatant was stored at −80°C until use.

Antibodies and reagents

Fluorescein isothiocyanate (FITC)-conjugated or phycoerythrin (PE)-conjugated anti-HLA-DR monoclonal antibodies (MoAbs), and PE-conjugated anti-CD11b MoAb were obtained from Becton Dickinson (Mountain View, CA). Anti-CD44 MoAbs were purchased from Seikagaku Co. (Tokyo, Japan). FITC-conjugated hyaluronic acid (FL-HA) was a generous gift from Dr Paul W Kincade (Oklahoma Medical Research Foundation, Oklahoma City, OK).

Flow cytometry

Surface expression of CD44 on alveolar macrophages was analysed by flow cytometry. BALF cells were stained with FITC-conjugated anti-HLA-DR antibody and biotinilated anti-CD44 MoAb, labelled with PE-conjugated streptavidin and analysed by flow cytometry. Surface expression of CD44 on alveolar macrophages was demonstrated both by gating HLA-DR+ cells and by using forward scatter versus side scatter, and then the percentages of alveolar macrophages expressing low CD44 (CD44 low+) were estimated. BAL cells were tested for HA-binding by flow cytometry after staining with FL-HA and PE-labelled anti-HLA-DR. As a CD44 specificity control, cells were also incubated with the blocking antibody, OS/37, followed by staining with FL-HA. The percentages of HA-binding alveolar macrophages were estimated by gating HLA-DR+ cells and by using forward scatter versus side scatter.

Measurement of sCD44 in BALF

The concentrations of sCD44 in BALF was measured with an ELISA kit (Bender MedSystems, Vienna, Austria).

Statistical analysis

All data were expressed as mean ± standard error (s.e.m.). Differences were identified by nonparametric tests, using Statview software package. The Mann–Whitney U-test or Wilcoxon signed rank test was used to examine differences between the means of unpaired or paired samples. Differences with probability values of <0·05 were considered significant.

Results

Characteristics of BALF cells

The BALF components of all groups are summarized in Table 1. The recovery rate of BALF was significantly lower in DPB patients than in healthy volunteers. The total number of cells per ml of BALF in patients with DPB was higher than that in healthy subjects. Differential cell counts revealed that the percentage of neutrophils in DPB BALF was significantly higher than in controls (P < 0·001, Table 1). The percentage of macrophages was significantly lower in patients with DPB (P < 0·001) than in healthy subjects, but the absolute number of macrophages in DPB was not significantly different from that in healthy volunteers (Table 1). The concentration of albumin in BALF from DPB patients was higher than in healthy subjects (P < 0·01, Table 1).

Table 1.

Characteristics of BALF cells in healthy volunteers and patients with diffuse panbronchiolitis (DPB) before and after macrolide therapy

DPB
Healthy volunteer Before therapy After therapy
Recovery (%) 64·4 ± 2·6 35·6 ± 4·9* 49·9 ±3·7†
Total cell count (× 105/ml) 1·7 ± 0·3 20·8 ± 10·4* 3·3 ± 1·0‡
Total AM count (× 105/ml) 1·5 ± 0·3 1·6 ± 0·2 1·5 ± 0·2
AM (%) 86·1 ± 2·3 20·1 ± 3·9** 62·6 ± 5·1‡
Ly (%) 11·2 ± 2·1 12·0 ± 2·0 17·9 ± 2·0
Neut (%) 1·7 ± 1·0 67·4 ± 4·9** 18·7 ± 5·5‡
Albumin (mg/dl) 23·0 ± 1·8 43·8 ± 5·5* 32·6 ± 5·5
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AM, alveolar macrophages; Ly, lymphocytes; Neut, neutrophils.

*

P < 0·01 compared with healthy volunteer subjects.

**

P < 0·001 compared with healthy volunteer subjects.

†

P < 0·05 compared with before macrolide therapy.

‡

P < 0·001 compared with before macrolide therapy.

Low CD44 concentration and CD44 underexpression on macrophages in BALF

The soluble form of CD44 (sCD44) is thought to originate from CD44 on the cell surface by a proteolytic cleavage mechanism [24]. We first compared the concentration of sCD44 in BALF from DPB patients with that from healthy volunteers. Significantly low concentrations of sCD44 were detected in BALF from DPB patients compared with normal controls (8·7 ± 1·3 ng/ml versus 14·2 ± 0·9 ng/ml, P < 0·005, Fig. 1). The mean ratio of sCD44 to albumin in BALF of DPB patients (25·3 ± 5·7 ng/mg) was also lower than that in healthy subjects (59·5 ± 6·0 ng/mg). Sixteen of the 19 patients with DPB underwent a second BAL after macrolide therapy. Macrolide treatment induced a significant reduction in the proportion of neutrophils in BALF (Table 1) and improvement of pulmonary function tests in patients with DPB data not shown). Furthermore, concentrations of sCD44 in BALF of DPB patients significantly increased after treatment with a macrolide (15·9 ± 1·8 ng/ml, P < 0·001, Fig. 1).

Fig. 1.

Fig. 1

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(a) Soluble CD44 (sCD44) levels in BALF from healthy volunteers and patients with diffuse panbronchiolitis (DPB) before and after macrolide therapy. Concentrations of sCD44 in BALF from healthy volunteers (□) and DPB (Inline graphic) were determined by ELISA. Values are expressed as mean ±s.e.m. (b) sCD44 concentrations were measured by ELISA in patients with DPB before and after macrolide therapy. Data represent values of paired samples obtained from the same patients.

In the next step, we compared CD44 expression on alveolar macrophages in BALF using two-colour flow cytometric analysis. In this study, HLA-DR was used as a macrophage cell surface marker. Interestingly, CD44 low+, CD11b high+, HLA-DR+ macrophages were found in BALF from DPB patients, but not in BALF from healthy volunteers (Fig. 2). The percentages of CD44 low+ alveolar macrophages in BALF of DPB patients were higher than in healthy volunteers (32·5 ± 7·2% versus 0·4 ± 0·1%, P < 0·005, Fig. 3). Furthermore, that subpopulation of alveolar macrophages decreased after macrolide treatment (7·0 ± 1·7%, P < 0·05, Fig. 3).

Fig. 2.

Fig. 2

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Characterization of alveolar macrophages in BALF from healthy volunteers (HV) and patients with diffuse panbronchiolitis (DPB). BALF cells from HV (left panels) and DPB (right panels) were analysed by two-colour flow cytometry. All dot plots were obtained by using forward scatter versus side scatter. The upper panels analyse dual expression of CD11b and CD44. The lower panels analyse dual expression of CD44 and HLA-DR. These results are representative of those obtained from six HV and seven patients with DPB.

Fig. 3.

Fig. 3

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CD44 expression on alveolar macrophages in healthy volunteers and patients with diffuse panbronchiolitis (DPB) before and after macrolide therapy. BALF cells from healthy volunteers (□) and patients with DPB before (▪) and after (Inline graphic) macrolide therapy were analysed by two-colour flow cytometry. Percentages of CD44 low+ alveolar macrophages were estimated by gating HLA-DR+ cells and by using forward scatter versus side scatter.

HA-binding ability of alveolar macrophages in patients with DPB

To examine the function of CD44 expressed on macrophages, we evaluated the CD44-dependent HA-binding ability of alveolar macrophages using FL-HA and flow cytometry. Almost all HLA-DR+ macrophages from BALF of healthy volunteers can bind HA in a CD44-dependent manner. In contrast, alveolar macrophages from patients with DPB exhibited a significant decrease in HA-binding ability (32·5 ± 7·8% versus 85·5 ± 1·9%, P < 0·005, Fig. 4). Furthermore, macrolide treatment normalized percentages of HA-binding macrophages in BALF of DPB patients (79·7 ± 5·0%, Fig. 4).

Fig. 4.

Fig. 4

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HA-binding ability of alveolar macrophages in healthy volunteers and patients with diffuse panbronchiolitis (DPB) before and after macrolide therapy. BALF cells from healthy volunteers (□) and patients with DPB before (▪) and after (Inline graphic) macrolide therapy were analysed using FL-HA and two-colour flow cytometry. Percentages of HA-binding alveolar macrophages (HA + AM) were estimated by gating HLA-DR+ cells using forward scatter versus side scatter.

Discussion

CD44 is a widely distributed cell adhesion molecule and speculated to be involved in migration and activation of lymphocytes, cytocidal activity of NK cells, and tumour metastasis [18]. As a transmembrane protein, CD44 can potentially transmit signals, and cross-linking of CD44 on monocytes by antibodies or natural ligands triggers release of insulin-like growth factor (IGF)-1, TNF-α and IL-1 β [25,26]. Furthermore ligation of cell surface CD44 by HA could induce IL-8 release by alveolar macrophages [22]. Therefore, CD44 could be a critical molecule for participation of monocytic lineage cells in inflammatory responses. To assess CD44 function, its HA-binding ability of alveolar macrophages was evaluated. Unexpectedly, we observed decreased HA-binding ability of alveolar macrophages from patients with DPB in this study. We recently reported that sialylation of CD44 negatively regulates its recognition of HA [20]. Furthermore, elevation of sialyl Lewis x in the lung of patients with DPB was demonstrated [27]. Further studies are required to evaluate the relationship between sialylation and HA-binding ability of alveolar macrophages in patients with DPB.

Alveolar macrophages are the major cell type known to internalize HA for degradation in normal lung, and CD44 participates in this process [28,29]. A decreased HA binding capacity of alveolar macrophages may account for the impairment of internalization and degradation of HA in bleomycin-induced lung injury in rat [30]. The local HA turnover in the lung may be important for the pathogenesis of patients with DPB. Recently a new function of CD44 expressed on macrophages was reported [31]. Phagocytosis of apoptotic neutrophils, but not apoptotic lymphocytes, by human monocyte-derived macrophages was rapidly augmented following ligation of CD44 by antibody in vitro. CD44 may regulate the clearance of apoptotic neutrophils during evolution of inflammatory responses following ligation by its natural ligand, HA in vivo. In this study we have reported for the first time the presence of CD44 low+ macrophages and decreased HA-binding of these cells in BALF of patients with DPB. This subpopulation of alveolar macrophages in patients with DPB may have dysfunction in the clearance of apoptotic neutrophils. Further studies are required to evaluate the relationship between HA-binding ability and the clearance of apoptotic neutrophils by alveolar macrophages. Accumulation of neutrophils is a vital component of the host response to infectious agents, but neutrophil-derived toxic substances inflict tissue damage and may induce chronic inflammation and deterioration in lung function associated with DPB [2,3]. Furthermore, low-dose macrolide therapy normalized neutrophil numbers as well as CD44 expression levels (Fig. 3) and HA-binding ability of alveolar macrophages in patients with DPB (Fig. 4). Taken together with the results of previous studies and our findings, dysfunctional CD44 in respect of HA-binding ability on alveolar macrophages could be involved in the pathogenesis of DPB by the decreased clearance of HA and apoptotic neutrophils. It was previously reported that erythromycin could induce differentiation of macrophages [32]. We recently reported that HA-binding ability of monocyte could be induced during cell activation or maturation [33]. The efficacy of erythromycin treatment for DPB may therefore be in part due to induction of macrophage maturation.

In conclusion, we have demonstrated in the present study low levels of sCD44 in BALF and CD44 expression on alveolar macrophages in patients with DPB. We also showed alveolar macrophage dysfunction with respect to HA-binding ability in patients with DPB. Further studies are required to clarify the role of alveolar macrophages in airway inflammation in patients with DPB.

Acknowledgments

The authors thank Dr Paul W Kincade for providing FL-HA. We are grateful for the technical assistance of Atsusi Yokoyama.

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