Relationship: 944
Title
Upstream event
Increase, Proliferation of goblet cellsDownstream event
Goblet cell hyperplasia
Key Event Relationship Overview
AOPs Referencing Relationship
| AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding |
|---|---|---|---|
| EGFR Activation Leading to Decreased Lung Function | adjacent | High | Low |
Taxonomic Applicability
| Term | Scientific Term | Evidence | Link | |
|---|---|---|---|---|
| human | Homo sapiens | High | NCBI | |
| mouse | Mus musculus | High | NCBI | |
| rat | Rattus norvegicus | High | NCBI |
Sex Applicability
| Sex | Evidence |
|---|---|
| Mixed | Moderate |
Life Stage Applicability
| Term | Evidence |
|---|---|
| Adult | Moderate |
Key Event Relationship Description
The term ‘hyperplasia’ refers to an increase in a tissue or organ that is linked to an increase in cell number or cell size. Therefore, increasing number of airway goblet cells that arise from proliferation can be considered a root cause of goblet cell hyperplasia (GCH).
Evidence Supporting this KER
Current and former smokers frequently exhibit goblet cell hyperplasia of the proximal airways (Saetta et al., 2000; Innes et al., 2006). While there is evidence that increased goblet cell proliferation may be the underlying cause of GCH (Silva and Bercik, 2012), the key players are still largely unexplored.
Biological Plausibility
Hyperplasia is increased cell production in a normal tissue or organ, therefore, goblet cell hyperplasia is an increase in the number of goblet cells.
Empirical Evidence
This KER is inferred - there is little empirical support. Studies often demonstrate goblet cells using cell type-specific immunostaining (MUC5AC) or GCH by histology or demonstrating increased Alcian blue and/or periodic acid Schiff's staining of tissues, concluding that GCH is present and linked to an increase in goblet cell numbers (Casalino-Matsuda et al., 2006; Camateros et al., 2007; Taniguchi et al., 2011; Hays et al., 2006; Tesfaigzi et al., 2004; Harkema and Hotchkiss, 1993).
Uncertainties and Inconsistencies
Neither the timing nor the exact molecular sequence of this KER are known at this time.
Quantitative Understanding of the Linkage
As this KER is inferred and either KE is demonstrated by semi-quantitative means at best, there is little to no quantitiative understanding.
Domain of Applicability
Goblet cell proliferation was reported in human, mouse and rat studies (Casalino-Matsuda et al., 2006; Ichinose et al., 2006; Camateros et al., 2007; Shatos et al., 2003; Ma et al., 2005).
References
Camateros, P., Tamaoka, M., Hassan, M., Marino, R., Moisan, J., Marion, D., Guiot, M.-C., Martin, J.G., and Radzioch, D. (2007). Chronic asthma-induced airway remodeling is prevented by toll-like receptor-7/8 ligand S28463. Am J Respir Crit Care Med 175, 1241–1249.
Harkema, J., and Hotchkiss, J. (1993). Ozone- and endotoxin-induced mucous cell metaplasias in rat airway epithelium: novel animal models to study toxicant-induced epithelial transformation in airways. Toxicol Lett 68, 251–263.
Ichinose, T., Sadakane, K., Takano, H., Yanagisawa, R., Nishikawa, M., Mori, I., Kawazato, H., Yasuda, A., Hiyoshi, K., and Shibamoto, T. (2006). Enhancement of mite allergen-induced eosinophil infiltration in the murine airway and local cytokine/chemokine expression by Asian sand dust. J Toxicol Environ Health A 69, 1571–1585.
Innes, A.L., Woodruff, P.G., Ferrando, R.E., Donnelly, S., Dolganov, G.M., Lazarus, S.C., and Fahy, J.V. (2006). Epithelial mucin stores are increased in the large airways of smokers with airflow obstruction. Chest 130, 1102-1108.
Ma, R., Wang, Y., Cheng, G., Zhang, H., Wan, H., and Huang, S. (2005). MUC5AC expression up-regulation goblet cell hyperplasia in the airway of patients with chronic obstructive pulmonary disease. Chin Med Sci J 20, 181–184.
Saetta, M., Turato, G., Baraldo, S., Zanin, A., Braccioni, F., Mapp, C., Maestrelli, P., Cavallesco, G., Papi, A., and Fabbri, L. (2000). Goblet cell hyperplasia and epithelial inflammation in peripheral airways of smokers with both symptoms of chronic bronchitis and chronic airflow limitation. Am J Respir Crit Care Med 161, 1016–1021.
Shatos, M.A., Gu, J., Hodges, R.R., Lashkari, K., and Dartt, D.A. (2008). ERK/p44p42 mitogen-activated protein kinase mediates EGF-stimulated proliferation of conjunctival goblet cells in culture. Invest Ophthalm & Vis Sci 49, 3351-3359.