Chest
Volume 130, Issue 4, October 2006, Pages 1102-1108
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Original Research
Epithelial Mucin Stores Are Increased in the Large Airways of Smokers With Airflow Obstruction

https://doi.org/10.1378/chest.130.4.1102Get rights and content

Background

Habitual cigarette smoking is associated with chronic mucus hypersecretion, but the relationship between mucus abnormalities and airflow obstruction in smokers is uncertain.

Methods

We collected bronchial biopsy samples and epithelial brushings from 24 smokers with and without airflow obstruction and 19 nonsmoking healthy control subjects. Epithelial mucin stores, mucin immunostains, and goblet cell morphology were quantified in bronchial biopsy samples using stereology, and mucin gene expression was quantified in epithelial brushings using real-time reverse transcriptase-polymerase chain reaction.

Results

Goblet cell size and number were higher than normal in smokers (both p < 0.05), leading to a 2.2-fold increase in the volume of stored mucin in the epithelium per surface area of basal lamina (1.94 ± 0.31 μm3/μm2 vs 4.32 ± 0.55 μm3/μm2 in control subjects vs smokers, p = 0.001). The increase in stored mucin occurred because of an increase in MUC5AC (p = 0.018) and despite a decrease in MUC5B (p < 0.0001). Stored mucin was significantly higher in the subgroup of smokers with airflow obstruction (p = 0.029) and correlated with FEV1/FVC even when controlling for diffusing capacity as a measure of emphysema (p = 0.034).

Conclusions

Epithelial mucin stores are increased in habitual smokers because of goblet cell hypertrophy and hyperplasia, and the pattern of mucin gene expression is abnormal. The highest epithelial mucin stores are found in smokers with airflow obstruction, suggesting a mechanistic link between epithelial mucin dysregulation and airflow obstruction.

Section snippets

Subjects

We enrolled 24 cigarette smokers (defined as current smoking of at least 10 cigarettes per day and a minimum history of 10 pack-years of exposure) and 19 nonsmoking control subjects (defined as < 10 pack-years of smoking with no smoking in the previous 10 years). For all subjects, inclusion criterion was age 30 to 65 years. Exclusion criteria were as follows: FEV1/FVC < 0.4; provocative concentration of methacholine resulting in 20% decrease in FEV1 from baseline value (PC20) [< 1 mg/mL];

Results

The baseline clinical characteristics of the 24 smokers and the 19 nonsmoking control subjects showed that more of the smokers were male, and that the smokers were older and had lower values for FEV1 and FEV1/FVC (Table 1). Although on average the smokers were more hyperresponsive to methacholine than the healthy subjects (Table 1), 17 of the 24 smokers had PC20 in the normal range (> 8 mg/mL). Sixteen of the 24 smokers had Dlco in the normal range (> 80% of predicted). All 19 healthy subjects

Discussion

We report that goblet cell hypertrophy and hyperplasia occur in the large airways of habitual cigarette smokers and result in epithelial mucin stores that are significantly higher than normal. The increase in stored mucin occurs because of an increase in MUC5AC and despite a decrease in MUC5B. Notably, the highest epithelial mucin stores are in the smoker subgroup with airflow obstruction, and mucin stores correlate with FEV1/FVC, even when controlling for diffusing capacity as a measure of

Acknowledgment

The authors thank the following staff at University of California, San Francisco for assistance with this study: Peggy Cadbury and Hofer Wong for recruiting subjects and for assistance with bronchoscopy; and Roderick Carter and Ronald Ferrando for assistance in tissue processing and analysis. The authors also thank Mimi Zeiger for editing the manuscript and Ingemar Carlstedt for the generous contribution of the monoclonal antibodies LUM2-3 and LUM5B-2.

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    Drs. Innes and Woodruff contributed equally to the article.

    This work was performed at the University of California, San Francisco.

    The authors have no financial or potential conflicts of interest.

    Financial support was provided by an RO1 grant (HL66564) to Dr. Fahy from the National Heart, Lung, and Blood Institute, and by a K23 award (RR17002) to Dr. Woodruff from the National Center for Research Resources. In addition, Dr. Innes was supported by an institutional training grant (HL-07185) from the National Heart, Lung, and Blood Institute.

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

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