Epidermal growth factor system regulates mucin production in airways

被引:466
作者
Takeyama, K
Dabbagh, K
Lee, HM
Agustí, C
Lausier, JA
Ueki, IF
Grattan, KM
Nadel, JA
机构
[1] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA
[3] Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94143 USA
关键词
D O I
10.1073/pnas.96.6.3081
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Goblet-cell hyperplasia is a critical pathological feature in hypersecretory diseases of airways. However, the underlying mechanisms are unknown, and no effective therapy exists. Here we show that stimulation of epidermal growth factor receptors (EGF-R) by its ligands, EGF and transforming growth factor alpha (TGF alpha), causes MUC5AC expression in airway epithelial cells both in in vitro and in vivo. We found that a MUC5AC-inducing epithelial cell line, NCI-H292, expresses EGF-R constitutively; EGF-R gene expression was stimulated further by tumor necrosis factor alpha (TNF alpha). EGF-R ligands increased the expression of;MUC5AC at both gene and protein levels, and this effect was potentiated by TNF alpha. Selective EGF-R tyrosine kinase inhibitors blocked MUC5AC expression induced by EGF-R ligands. Pathogen-free rats expressed little EGF-R protein in airway epithelial cells; intratracheal instillation of TNF alpha induced EGF-R in airway epithelial cells, and subsequent instillation of EGF-R ligands increased the number of goblet cells, Alcian blue-periodic acid-Schiff staining (reflecting mucous glycoconjugates), and MUC5AC gene expression, whereas TNF alpha, EGF, or TGF alpha alone was without effect. In sensitized rats, three intratracheal instillations of ovalbumin resulted in EGF-R expression and goblet-cell production in airway epithelium. Pretreatment with EGF-R tyrosine kinase inhibitor, BIBX1522, prevented goblet-cell production both in rats stimulated by TNF alpha-EGF-R Ligands and in an asthma model. These findings suggest potential roles for inhibitors of the EGF-R cascade in hypersecretory diseases of airways.
引用
收藏
页码:3081 / 3086
页数:6
相关论文
共 36 条
[1]   Goblet cell degranulation after antigen challenge in sensitized guinea pigs - Role of neutrophils [J].
Agusti, C ;
Takeyama, K ;
Cardell, LO ;
Ueki, I ;
Lausier, J ;
Lou, YP ;
Nadel, JA .
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 1998, 158 (04) :1253-1258
[2]   MARKED GOBLET CELL HYPERPLASIA WITH MUCUS ACCUMULATION IN THE AIRWAYS OF PATIENTS WHO DIED OF SEVERE ACUTE ASTHMA ATTACK [J].
AIKAWA, T ;
SHIMURA, S ;
SASAKI, H ;
EBINA, M ;
TAKISHIMA, T .
CHEST, 1992, 101 (04) :916-921
[3]   Expression of epidermal growth factor and epidermal growth factor receptor immunoreactivity in the asthmatic human airway [J].
Amishima, M ;
Munakata, M ;
Nasuhara, Y ;
Sato, A ;
Takahashi, T ;
Homma, Y ;
Kawakami, Y .
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 1998, 157 (06) :1907-1912
[4]  
BOAT TF, 1994, TXB RESP MED, pCH43
[5]   CYTOKINES IN SYMPTOMATIC ASTHMA AIRWAYS [J].
BROIDE, DH ;
LOTZ, M ;
CUOMO, AJ ;
COBURN, DA ;
FEDERMAN, EC ;
WASSERMAN, SI .
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 1992, 89 (05) :958-967
[6]   Human monocytes and neutrophils store transforming growth factor-alpha in a subpopulation of cytoplasmic granules [J].
Calafat, J ;
Janssen, H ;
StahleBackdahl, M ;
Zuurbier, AEM ;
Knol, EF ;
Egesten, A .
BLOOD, 1997, 90 (03) :1255-1266
[7]  
Cardell BS, 1959, THORAX, V14, P341
[8]  
DONATO NJ, 1992, CELL GROWTH DIFFER, V3, P259
[10]   MUCUS HYPERSECRETION IN BRONCHIECTASIS THE ROLE OF NEUTROPHIL PROTEASES [J].
FAHY, JV ;
SCHUSTER, A ;
UEKI, I ;
BOUSHEY, HA ;
NADEL, JA .
AMERICAN REVIEW OF RESPIRATORY DISEASE, 1992, 146 (06) :1430-1433