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Am. J. Respir. Crit. Care Med., Volume 163, Number 2, February 2001, 517-523

Mild and Moderate Asthma Is Associated with Airway Goblet Cell Hyperplasia and Abnormalities in Mucin Gene Expression

CLAUDIA L. ORDOÑEZ, RAMIN KHASHAYAR, HOFER H. WONG, RON FERRANDO, REEN WU, DALLAS M. HYDE, JON A. HOTCHKISS, YIFAN ZHANG, ALEXANDER NOVIKOV, GREGORY DOLGANOV, and JOHN V. FAHY

Departments of Pediatrics and Medicine and Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California; Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California at Davis, Davis, California; Laboratory for Experimental and Toxicologic Pathology, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan; and Genelabs Technologies, Redwood City, California

Excessive airway mucus is an important cause of morbidity and mortality in asthma, but the relationship between accumulation of mucus and goblet cell size, number, and function is incompletely understood. To address these questions, stored mucin in the epithelium and goblet cell size and number were measured morphometrically, and mucin gene expression was measured by polymerase chain reaction and immunohistochemistry in endobronchial biopsies from 13 subjects with mild and moderate asthma and from 12 healthy control subjects. Secreted mucin was measured in induced sputum. We found that stored mucin in the airway epithelium was three times higher than normal in the subjects with asthma (p < 0.005). Goblet cell size was similar in both groups, but goblet cell number was significantly higher in the subjects with asthma (93,043 ± 15,824 versus 41,959 ± 9,230/mm3, p < 0.05). In mild asthma (FEV1 >=  80% pred, n = 7), the level of stored mucin was as high as in moderate asthma (FEV1 < 80% pred, n = 6), but the level of secreted mucin was significantly lower (28.4 ± 6.3 versus 73.5 ± 47.5 µg/ml, p < 0.05). Secreted mucin was inversely correlated with stored mucin for the whole asthma group (rs = -0.78, p = 0.007). MUC5AC was the predominant mucin gene expressed in healthy subjects and subjects with asthma, and MUC5AC protein was increased in the subjects with asthma. We conclude that even mild asthma is associated with goblet cell hyperplasia and increased stored mucin in the airway epithelium, whereas moderate asthma is associated with increased stored mucin and secreted mucin. These findings suggest that acute degranulation of hyperplastic goblet cells may represent a mechanism for asthma exacerbations in mild and moderate asthma and that chronic degranulation of goblet cells may contribute to chronic airway narrowing in moderate asthma.




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