Upstream eventOccurrence, Metaplasia of goblet cells
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
Key Event Relationship Description
Goblet cell metaplasia results in an increased number of goblet cells and secretion of mucus. This can lead to mucus hypersecretion, narrowing of airways and difficulty breathing (Nadel, 2013). There is an inverse relationship between goblet cell metaplasia and FEV1, a measure of lung function (Nagai et al., 1995). Smokers have an increased number of goblet cells in peripheral airways which is negatively correlated with low FEV1/FVC (lung function) which could be caused by mucus hypersecretion (Saetta et al., 2000).
Evidence Supporting this KER
It is biologically plausible that increased metaplasia leads to mucus hypersecretion. The increased number of goblet cells in metaplastic tissue secrete increased mucus. Studies have found low mitotic rates along with increased number of goblet cells, suggesting differentiation into and not proliferation of goblet cells is occurring (Shimizu et al., 1996), (Lamb and Reid, 1968).
Include consideration of temporal concordance here
There is no empirical support since clinical studies do not investigate cellular differentiation into goblet cells and functional measures of mucus hypersecretion within the same study.
Uncertainties and Inconsistencies
Quantitative Understanding of the Linkage
Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?
The KEs in this relationship are considered equivalent in most animal studies (increased mucus is a measure for metaplasia as well as mucus hypersecretion). A study measuring differentiated goblet cells and the relationship to increased mucin production would add to the quantitative understanding of how much mucus is produced per differentiated goblet cell. A clinical study measuring increased mucus in the lung and the relationship to sputum production would add to the quantitative understanding of how internal mucus relates to sputum production, however it would be unclear whether increased mucus is due to hyperplasia or metaplasia unless proliferation and differentiation is specifically tested.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Many studies have shown metaplasia and mucus hypersecretion in human, mouse and rat. Studies show a correlative relationship rather than a causal one, and sometimes these terms are used synonymously.
1. Lamb, D., and Reid, L. (1968). Mitotic rates, goblet cell increase and histochemical changes in mucus in rat bronchial epithelium during exposure to sulphur dioxide. J. Pathol. Bacteriol. 96, 97–111.
2. Nadel, J. (2013). Mucous hypersecretion and relationship to cough. Pulm Pharmacol Ther 26, 510–513.
3. Nagai, A., Thurlbeck, W.M., and Konno, K. (1995). Responsiveness and variability of airflow obstruction in chronic obstructive pulmonary disease. Clinicopathologic correlative studies. Am. J. Respir. Crit. Care Med. 151, 635–639.
4. 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.
5. Shimizu, T., Takahashi, Y., Kawaguchi, S., and Sakakura, Y. (1996). Hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium induced by endotoxin. Am. J. Respir. Crit. Care Med. 153, 1412–1418.