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University of Tsukuba Tsukuba, Japan
Correspondence to: Kiyohisa Sekizawa, MD, Department of Pulmonary Medicine, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1–1-1 Tennoudai Tsukuba, Ibaraki, 305-8575, Japan; e-mail: kiyo-se{at}md.tsukuba.ac.jp
To the Editor:
We read with interest the article by Kim et al1 in CHEST (September 2004) in which the authors examined the relationship between epidermal growth factor receptor (EGFR) expression in the bronchiolar epithelium with neutrophilic inflammation and mucus hypersecretion in the tissues of patients with diffuse panbronchiolitis (DPB). DPB is a COPD that is characterized clinically by chronic cough, excessive sputum, and dyspnea. It is prevalent in Japan and Korea but is rare in other countries. If left untreated, DPB is fatal. The introduction of low-dose, long-term macrolide therapy in 1984 caused the survival rate to rise markedly.2 Since then, most studies had concentrated on the treatment mechanisms while very few had been looking for the mechanisms of the disease itself. Therefore, the effort of Kim et al1 to investigate the mechanism of mucus hypersecretion in DPB and its relation to the EGFR-mucin pathway should be acknowledged. However, several points of weakness in their study should be debated.
First, it is known that in healthy lungs few cells will be positively stained with alcian blue/periodic acid-Schiff (AB/PAS) stains. The markedly high percentage of mucin staining in the bronchial epithelium of the control samples in this study (50%) indicate clearly that there was something wrong with these samples. The authors mention that the samples were taken from healthy portions of the lobectomy specimens from six nonsmoking patients with adenocarcinoma. It seems that even the uninvaded lung tissues of the adenocarcinoma patients were showing secondary changes, so clearly these patients were not the proper control subjects. The authors could use the easier option of collecting fiberoptic bronchoscopic bronchial biopsy specimens from completely healthy volunteers.
Second, Figure 7 seems to contradict what is written in the results and is shown in Figure 4. While in the results it is written that the mean (± SD) percentage of the luminal area occupied by AB/PAS and MUC5AC stains was 84.6 ± 7.63% in the DPB group, which is beautifully shown in Figure 4; Figure 7 shows hardly any intraluminal mucin or MUC5AC staining in either group.
Third, in the control subjects, the finding that 50% of the bronchiolar epithelial area was occupied by epithelium stained with AB/PAS and MUC5AC while EGFR expression was absent is difficult to understand. It had been shown that the airway mucin production in response to various stimuli is mediated through the EGFR cascade.3 EGFR was shown to be related to the mucus production in goblet cells, not to the degranulation of the mucin granules.4 The authors’ assumption that goblet cell hyperplasia occurred due to some transient inflammation, and that degranulation did not occur due to inflammation subsidence, which led to a down-regulation of EGFR, is too hypothetical, and it only indicates that these were not suitable control samples.
In conclusion, we think that another, better controlled prospective study that will also examine the BAL fluid for counts of neutrophils and other cells, as well as for cytokines such as interleukin-8, and their correlation to the EGFR expression and mucus secretion is still needed.
References
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