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(Chest. 2004;126:888-895.)
© 2004 American College of Chest Physicians

Relation of Epidermal Growth Factor Receptor Expression to Mucus Hypersecretion in Diffuse Panbronchiolitis*

Je-Hyeong Kim, MD; Ki-Hwan Jung, MD; Joung-Ho Han, MD; Jae-Jeong Shim, MD; Kwang-Ho In, MD; Kyung-Ho Kang, MD, FCCP and Se-Hwa Yoo, MD

* From the Department of Internal Medicine (Drs. Kim, Jung, Shim, In, Kang, and Yoo), Division of Pulmonology, College of Medicine, Korea University, Seoul, Korea; and the Department of Diagnostic Pathology (Dr. Han), College of Medicine, Sungkyunkwan University, Suwon, Korea.

Correspondence to: Jae-Jeong Shim, MD, Pulmonary Division, Department of Internal Medicine, Korea University Guro Hospital, 97 Gurodong-gil, Guro-gu, Seoul, Korea 152–703; e-mail: jaejshim{at}kumc.or.kr


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study object: Diffuse panbronchiolitis (DPB) is a hypersecretory airway disease, and the mechanism of mucus hypersecretion in DPB is poorly understood. Moreover, mucin synthesis in the airways has been reported to be regulated by neutrophilic inflammation-induced epidermal growth factor receptor (EGFR) expression, and the degranulation of goblet cells is known to be mediated by neutrophilic elastase. In this study, we examined the relationship between EGFR expression in the bronchiolar epithelium with neutrophilic inflammation and mucus hypersecretion in the tissues of DPB patients.

Design: The tissue specimens of 13 DPB patients and 6 healthy control subjects were examined by alcian blue/periodic acid-Schiff (AB/PAS) staining for mucous glycoconjugates, and by immunohistochemical staining for MUC5AC, EGFR, tumor necrosis factor-{alpha}, and CD16 on neutrophils.

Results: Neutrophilic inflammation was significantly higher in the tissue of DPB patients than in that of control subjects (p = 0.002). In the bronchiolar epithelium, goblet cell metaplasia, by AB/PAS staining and mucin MUC5AC expression, was significantly higher than that in control subjects (p = 0.001 and p = 0.002, respectively). In addition, the morphometric quantification of intraluminal mucus secretion showed that the areas of the bronchiolar lumen occupied by mucus secretion were significantly increased in the tissue of DPB patients (p = 0.001), suggesting goblet cell degranulation. EGFR expression was observed in the bronchiolar epithelium of DPB patients, but not in that of control subjects.

Conclusions: In DPB, we suggest that mucus hypersecretion due to goblet cell metaplasia is closely associated with neutrophilic inflammation and the expression of EGFR. The study also shows that intraluminal secretion due to the degranulation of goblet cells degranulation is related to neutrophilic inflammation.

Key Words: diffuse panbronchiolitis • epidermal growth factor receptor • goblet cell metaplasia • mucus hypersecretion


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Diffuse panbronchiolitis (DPB) is a chronic progressive disease of the lower respiratory tract, and is characterized by a chronic productive cough, exertional dyspnea, and disseminated reticulonodular densities, as determined by chest radiography. In particular, the production of sputum is one of the main clinical manifestations of DPB. Normally, mucus secretion plays an important role in mucosal protection by forming a viscoelastic gel that spreads on the airway luminal surfaces of airways, which interacts with cilia to form the mucociliary transport system. However, excessive mucus secretions contribute to the pathogenesis of many chronic inflammatory airway diseases.1

Mucin synthesis in airways has been reported to be regulated by the epidermal growth factor receptor (EGFR) cascade. According to in vivo and in vitro studies, the expression of EGFR in the bronchiolar epithelium is increased by tumor necrosis factor (TNF)-{alpha}, which is produced by activated neutrophils. Moreover, the activation of EGFR tyrosine kinase by its ligands or by oxidative stress leads to mucus hypersecretion and goblet cell metaplasia,2345 and mature goblet cells are degranulated by neutrophilic elastase.67 However, although these relationships have been observed in the epithelium of asthmatic human bronchi8 and of nasal polyps,9 studies in patients with other chronic inflammatory airway diseases are limited.

Histologically, DPB is characterized by chronic inflammation, localized mainly in the respiratory bronchioles and adjacent centrilobular regions with plasma cell and lymphocyte infiltration.10 According to pathologic and BAL fluid (BALF) studies, aggregates of neutrophils admixed with mucin are frequently present in the airway lumen,11 and, in particular, DPB patients were found to have significantly higher percentages of neutrophils in BALF.12131415 These results suggest a central role for neutrophils in the lower respiratory tract in the pathogenesis of DPB.

The purpose of this study was to elucidate the mechanism of mucus hypersecretion in DPB by examining the relations among neutrophilic inflammation, EGFR expression of the bronchiolar epithelium, and goblet cell metaplasia.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Subjects
Thirteen DPB tissue specimens archived at the Department of Pathology, Korea University Medical Center, and at the Samsung Medical Center in the form of paraffin blocks were used for this study. The mean (± SD) age of patients at diagnosis was 38.8 ± 11.9 years, and the male/female ratio of patients was 8:5. All medical records and roentgenographic films were reviewed. All patients had the characteristic symptoms (ie, a chronic cough, large amounts of sputum, and paranasal sinusitis). Roentgenographically, disseminated fine nodular shadows were observed in all patients. A diagnosis of DPB was made by pathologic examination of open or thoracoscopic lung biopsy specimens. "The unit lesion" theory that chronic inflammation mainly affects respiratory bronchioles with distinctive interstitial accumulation of foam cells in the walls of respiratory bronchioles, adjacent alveolar ducts, and alveoli has been used as a histologic criterion.10 No patient had a history of macrolide treatment or smoking prior to the diagnosis of DPB. Normal portions of the lobectomy specimens from six nonsmoking female patients with adenocarcinoma were used as the control group tissues. No control subject had evidence of an infectious lung disease by medical record review or by roentgenographic examination. These specimens were taken by a pathologist from the periphery of excised tissues. The normality of these specimens was then confirmed by histologic examination, and they showed no evidence of cancer invasion. The investigation protocol used was approved by the Korea University Medical Center Board of Medical Research and by the Research Ethics Committee.

Standard Morphologic Evaluation and Immunohistochemical Staining
Five-micrometer paraffin sections were obtained, deparaffinized, and stained (Diff-Quik Stain Set; International Reagent Corporation; Tokyo, Japan) for morphologic studies, and then with alcian blue/periodic acid-Schiff (AB/PAS) for mucous glycoconjugates.

Immunohistochemical staining was performed as described previously.5 Sections were stained with monoclonal antibodies to CD16 (dilution, 1:250) [Biosource International; Camarillo, CA], EGFR (dilution, 1:250) [Calbiochem; La Jolla, CA], and MUC5AC (dilution, 1:500) [clone 45 M1; Neomarkers; Fremont, CA]. Immunohistochemical staining for TNF-{alpha} was performed using a polyclonal rabbit antihuman antibody to TNF-{alpha} (dilution, 1:1000) [Genzyme Corp; Cambridge, MA].

Quantification of Stained Areas in the Bronchiolar Epithelium and Intraluminal Mucus Secretion
Recruited neutrophils were assessed by counting CD16-stained cells in the bronchiolar epithelium. For each specimen, we obtained the images of 10 consecutive high-power fields at a magnification of x 400 and counted positively stained cells. The results are expressed as the number of positively stained cells per 0.25 mm2 bronchiolar epithelium. Quantification of AB/PAS stained areas, and of MUC5AC and EGFR immunoreactivities were performed using a semiautomatic imaging system. Sections were counted by a single blinded observer on two separate occasions in a coded random manner, as described previously.16 Images of the bronchiolar epithelium were recorded from 10 high-power fields at x 400. We measured areas stained by AB/PAS, MUC5AC, and EGFR, and the total bronchiolar epithelial area (with results expressed as a percentage of area stained by AB/PAS) was measured by an antibody to MUC5AC or by an antibody to EGFR. Analyses were performed using the public domain IMAGE program of the National Institutes of Health.17

The amount of AB/PAS-stained mucus in the airway lumen was assessed by using a semiautomatic imaging system, and the results are expressed as percentages of the areas occupied vs the total mucus secretion areas in the bronchioles.

Statistical Analysis
All data are expressed as the mean ± SD. Statistical analysis was performed using the nonparametric Mann-Whitney U method for intergroup comparisons. A p value of < 0.05 was accepted as being statistically significant.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Neutrophilic Infiltration and TNF-{alpha} Immunohistochemical Localization
Because activated neutrophils have been implicated in goblet cell degranulation and mucin production, we examined neutrophilic infiltration in the specimens by using a monoclonal antibody to CD16. The mean neutrophilic infiltrations in the bronchiolar epithelium of DPB patients and control subjects were 73.84 ± 2.84 and 41.34 ± 4.78 per 0.25 mm2, respectively, and this was significant (p = 0.002) [Fig 1, 2 ]. In the bronchiolar lumen, many CD16-positive cells were observed in the DPB group, but CD-16 immunoreactivity was scant in the control group.



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  		Figure 1. Neutrophilic infiltration as determined using a monoclonal antibody to CD16 in control subjects (white column) and DPB patients (black column). In the DPB group, the number of positively stained CD16 cells were significant (* = p = 0.002). Data are reported as the number of positive cells per 0.25 mm2 bronchiolar epithelium.

 


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  		Figure 2. Neutrophilic infiltration in the DPB group, as determined by using a monoclonal antibody to CD16. Increased CD-16-positive cells (brown) were observed in the bronchial epithelial and subepithelial areas (original x 400).

 
No TNF-{alpha} immunoreactivity was observed in control group specimens, but the tissues of DPB patients showed TNF-{alpha} immunoreactivity in inflammatory cells in the epithelial and subepithelial layers (Fig 3 ). Most of the stained cells were neutrophils.



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  		Figure 3. TNF-{alpha} immunohistochemical staining. After staining with a polyclonal antibody to TNF-{alpha}, the DPB specimens showed TNF-{alpha} immunoreactivity in inflammatory cells in the epithelial and subepithelial layers. The cells involved were mainly neutrophils (original x 1,000).

 
Goblet Cell Metaplasia and Bronchiolar Epithelial Mucin MUC5AC Expression
Goblet cells were observed in the specimens of both control subjects and DPB patients. Goblet cells from the control group showed distended cytoplasms with dense granule aggregation. However, in the DPB group the cytoplasm was thinner. The mean area occupied by AB/PAS stain was 8.31 ± 3.36% in the DPB group and 50.0 ± 5.77% in the control group, which was significant (p = 0.001), whereas the mean MUC5AC expression was 11.46 ± 4.68% and 53.33 ± 6.67% of the epithelial area in the DPB and control groups (p = 0.002) [Fig 4, 5 ].



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  		Figure 4. Comparison of AB/PAS staining (left panels) and MUC5AC protein immunolocalization (right panels) in control subjects (lower panels) and DPB patients (upper panels). Goblet cell metaplasia by determined by AB/PAS staining was significantly lower in DPB patients, as was MUC5AC expression (bar = 100 µm).

 


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  		Figure 5. Percentages of areas of the bronchiolar epithelium stained with AB/PAS and MUC5AC, and intraluminal mucus secretion in the control group and in the DPB group. Goblet cell metaplasia was examined by AB/PAS staining. Mucin MUC5AC expression was significantly lower in DPB (* = p = 0.001; ** = p = 0.002), but in the bronchiolar lumen the percentages of luminal area stained by AB/PAS and MUC5AC were significantly higher in the DPB group ({dagger} = p = 0.001).

 
Intraluminal Secretions and Mucin MUC5AC Expression in Bronchioles
In the DPB group, copious secretions and mucus plugs were observed in the bronchiolar lumen. Large AB/PAS- and MUC5AC-stained areas were observed in the lumens of the DPB group, but the control group showed minimal evidence of secretion with scant AB/PAS- and MUC5AC-staining. The percentages of luminal area occupied by AB/PAS and MUC5AC stains were 84.6 ± 7.63% in the DPB group and 4.71 ± 1.31% in the control group, showing a significantly higher value in the DPB group (p = 0.001) [Fig 4 , 5].

EGFR Expression in the Bronchiolar Epithelium
In the control group, no EGFR immunoreactivity was observed in tissues, but the tissues of the DPB group expressed EGFR immunoreactivity in the bronchiolar epithelium. The mean percentage area of EGFR-positive staining in the bronchiolar epithelium was 9.54 ± 4.95% (Fig 6, 7 ).



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  		Figure 6. Percentage of EGFR areas stained in the bronchial epithelium in the control group (open column) and the DPB group (filled column). In the control group, no EGFR immunoreactivity was observed in tissue, but EGFR immunoreactivity was expressed in the bronchial epithelium of the DPB group.

 


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  		Figure 7. Overall comparison of AB/PAS (left panels), MUC5AC (middle panels), and EGFR (right panels) staining of the bronchiolar epithelium in the control group (lower panels) and the DPB group (upper panels). The DPB group expressed lower levels of AB/PAS and MUC5AC than the control group, and was positive for EGFR staining, whereas the control group did not (bar = 100 µm).

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, DPB was found to be correlated with neutrophilic infiltration, bronchiolar epithelial EGFR expression, and intraluminal areas occupied by AB/PAS and MUC5AC staining. Control tissues, on the other hand, did not express EGFR in the epithelium, and showed lower neutrophilic infiltration and scant intraluminal secretion.

DPB has been established as a definite clinical entity, a sinobronchial syndrome characterized by chronic sinusitis and bronchiolar inflammation. The diagnostic hallmarks of DPB are inflammatory changes in peribronchiolar tissue. Such changes include a thickening of the wall of respiratory bronchioles, and of peribronchiolar infiltration by lymphocytes, plasma cells, and inflammatory cytokines.18 Moreover, BALF studies12131415 have reported that DPB patients have significantly higher concentrations of neutrophilic chemoattractants, neutrophils, and neutrophilic proteolytic products. These results suggest a central role for neutrophils in the pathogenesis of DPB.

A large amount of sputum is a major characteristic of DPB, as it is in other chronic inflammatory airway diseases. Hypersecretion by goblet cells causes airway mucus plugging, especially in the peripheral airways where large numbers of secreting goblet cells can more easily cause obstruction. However, the mechanisms of airway mucus hypersecretion and goblet cell metaplasia are poorly understood. Nevertheless, a novel mechanism has been reported that involves the regulation of mucin synthesis and goblet cell metaplasia in human airway epithelial cells, and in the tracheal epithelium. Several in vivo and in vitro studies have implicated EGFR signaling in airway goblet cell metaplasia. TNF-{alpha} produced by activated neutrophils up-regulates EGFR expression in airway epithelial cells, and when EGFR is expressed in the epithelium, the activation of the receptor can occur by two distinct processes. One involves ligand-dependent autophosphorylation mediated by EGFR ligands,319 which are produced by many other cells,202122 and the other involves ligand-independent transactivation induced by various stimuli,23242526 such as by oxidative stress (ie, H2O2).342728 The downstream signaling cascade, which involves multiple steps, results in mucin gene transcription and mucin protein synthesis.2345

The degranulation of goblet cells into the bronchiolar lumen occurs under conditions of active neutrophilic inflammation, a process that has been reported to be mediated by neutrophilic elastase.67 Neutrophil chemoattractants, such as interleukin (IL)-8, induce elastase to move from azurophilic granules in the cytoplasm to the neutrophil surface, and increase the expressions of adhesion molecules, such as goblet cell intracellular adhesion molecule-1 and the neutrophil Mac-1. Contact interactions between activated neutrophils and goblet cells, which cause the release of elastase from the neutrophil surface, occur via these adhesion molecules. This then diffuses to goblet cells and causes degranulation. In the present study, DPB tissues were found to be closely related with neutrophilic infiltration, TNF-{alpha} immunoreactivity, EGFR expression in the bronchiolar epithelium, and the degree of intraluminal secretion. These findings suggest that neutrophilic inflammation induces EGFR expression, and that EGFR activation might play a major role in hypersecretion in DPB patients. Because this study was performed retrospectively using pathologic specimens, its limitation is that BALF analysis for IL-8 and elastase, which are related to neutrophilic recruitment and goblet cell degranulation, was not performed. However, increased levels of IL-8 and elastase activity have been reported1415 on several occasions in the BALF of DPB patients.

Despite efforts to secure lung tissue from nonsmokers with healthy bronchioles, the control tissues showed that around 50% of the bronchiolar epithelial area was occupied by epithelium stained with AB/PAS and MUC5AC. It is difficult to provide an explanation for this result. Morphologic studies showed no evidence of goblet cell degranulation, and EGFR expression was absent. Although no evidence of infectious lung disease was found in the medical records or by roentgenography, we presume that goblet cell hyperplasia occurred due to some transient inflammation, but that degranulation did not occur due to inflammation subsidence. Moreover, it is supposed that the waning of an inflammation after goblet cell metaplasia led to a down-regulation of EGFR. It has been reported that some goblet cells exist in the epithelium of human nasal tissues9 and rat nasal tissues,29 and in the lower airways of healthy human subjects,8 but such an epithelium does not express EGFR. In degranulation-free conditions, previously expressed EFGR is reported to be down-regulated.929 However, after neutrophil-dependent goblet cell degranulation, EGFR expression is intense, and this was found to be associated with regranulation and neutrophil influx.9 DPB is associated with persistent neutrophilic inflammation, and for this reason it is presumed that EGFR expression is substantial in DPB patients and that continued degranulation causes intraluminal secretion. Moreover, persistent neutrophilic inflammation was found to induce goblet cell degranulation and regranulation cycling.929 As a result, DPB tissues were found to expressed less epithelial and more intraluminal AB/PAS and MUC5AC staining. However, the control group showed goblet cells in the epithelium and scant intraluminal secretion, without evidence of degranulation. The shapes of goblet cells were found to be slender in the DPB tissues and distended with dense granule aggregation in the control group. Because, in the present study, the degree of epithelial goblet cell metaplasia was expressed in terms of areas stained with AB/PAS and MUC5AC, degranulation in DPB tissues might result in a reduced stained area despite an increase in the number of goblet cells. On the other hand, in the control group, it is possible that the stained area was determined to have increased due to the absence of degranulation. Intraluminal mucus secretion and plugging are characteristic features of hypersecretory airway diseases like bronchial asthma30313233 and chronic bronchitis,34 and the present study shows a similar pattern of mucus plugging the airways of DPB patients.

The causes and pathogenesis of bronchiolar inflammation remain unknown. Human leukocyte antigen (HLA) analysis in DPB patients suggests that one or some of the genes controlling the susceptibility to or the immune responsiveness of DPB may be located near HLA loci, or that the HLA molecule itself plays an important role in the pathogenesis of the disease.35 Although Haemophilus influenzae and Pseudomonas aeruginosa frequently infect the airway, cultures of sputum do not always reveal bacteria. Fujii and coworkers36 have reported that bacterial infection was detected in only 16 of the 28 DPB patients studied. If bacteria are isolated, they are usually found to be strains of P aeruginosa, an opportunistic pathogen that frequently occurs in cases of severe bacterial exacerbations in patients with advanced chronic bronchitis.3637 Macrolides are known to contribute to improvements in the prognosis of DPB. These agents, which include erythromycin, are antibiotics with a bactericidal effect. In the case of erythromycin treatment, however, its clinical mode of action cannot be attributed to a bactericidal effect for the following reasons. First, the disease can improve without the elimination of bacteria. Second, improvement can be found even in patients with P aeruginosa infection. Third, the maximal concentration of erythromycin in serum or sputum, which is approximately 1 µg/mL, is lower than the minimum inhibitory concentration for major species of bacteria.38 Macrolides dose-dependently inhibit mucus secretion,39 and also reduce neutrophilia, neutrophilic elastase, and cytokines, especially IL-8, in BALF.1340414243 However, these two effects of macrolides were studied separately, and thus the relationships between these actions are poorly understood. Despite its many limitations and the need for further evaluations, our study suggests that macrolides suppress neutrophilic inflammation by decreasing IL-8, and that this results in the inhibition of EGFR-mediated goblet cell metaplasia and in degranulation in DPB patients.

In conclusion, we present the hypothesis that neutrophilic inflammation is closely associated with EGFR-dependent goblet cell metaplasia and degranulation in DPB patients.


   Footnotes
 
Abbreviations: AB/PAS = alcian blue/periodic acid-Schiff; BALF = BAL fluid; DPB = diffuse panbronchiolitis; EGFR = epidermal growth factor receptor; HLA = human leukocyte antigen; IL = interleukin; TNF = tumor necrosis factor

This research was supported by a Korea University Grant.

Received for publication January 29, 2003. Accepted for publication March 30, 2004.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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