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Relationship: 2471
Title
Goblet cell metaplasia leads to Chronic, Mucus hypersecretion
Upstream event
Downstream event
AOPs Referencing Relationship
Taxonomic Applicability
Sex Applicability
| Sex | Evidence |
|---|---|
| Mixed | Moderate |
Life Stage Applicability
| Term | Evidence |
|---|---|
| All life stages | Moderate |
Goblet cell metaplasia refers to the result of transdifferentiation, i.e., the generation of specialized cell types, such as goblet cells, from other specialized cells, such as ciliated and club cells (Evans et al., 2004; Tesfaigzi, 2006), and is a key feature of the chronically remodeled airways in both asthma and COPD (Kuchibhotla and Heijink, 2020). Chronic mucus hypersecretion is also a main feature of chronic lung diseases, and the presence of goblet cell metaplasia in the lungs of chronic obstructive pulmonary disease, asthma and cystic fibrosis patients has been inferred as cause for sustained mucus production (Rose and Voynow, 2006; Boucherat et al., 2013; Munkholm and Mortensen, 2014).
| ID | Experimental Design | Species | Upstream Observation | Downstream Observation | Citation (first author, year) | Notes |
|---|
| Title | First Author | Biological Plausibility |
Dose Concordance |
Temporal Concordance |
Incidence Concordance |
|---|
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
Uncertainties and Inconsistencies
In some cases, it appears that authors use the terms "goblet cell hyperplasia" and "goblet cell metaplasia" interchangeably, making the evaluation of the available evidence difficult.
Because goblet cell metaplasia is also a feature of epithelial cell remodeling in the context of wound healing, its appearance can be transient. At least one study indicates that goblet cell hyperplasia is also found in healthy non-smokers (never- and former smokers), where it appears as isolated foci—as opposed to the more extensive involvement of the airway epithelium seen in e.g. COPD patients (Polosukhin et al., 2011).
Unknown
Our quantitative understanding of this KER is limited by the fact that few studies interrogate causality between goblet cell metaplasia and increased mucin production. To our knoweldge, there is no comprehensive, systematic study of the dose-response relationship. This may be primarily due to the fact that goblet cell metaplasia is a qualitative finding on histopathological examination and cannot be as easily quantified as, for example, the number of cells that stain positively with an anti-MUC5AC antibody as a marker for mucin production.
Response-response Relationship
Daily 30-min treatments of primary human bronchial epithelial cells at the air-liquid interface with 0.6 mM xanthine and 0.5 units xanthine oxidase for 3 days resulted in goblet cell metaplasia as evidenced by an increase in the numbers of MUC5AC-positive cells from 3.3 ± 1.2%to 21.6 ± 3.4%, and increased MUC5AC protein expression (32.5 + 9.3% above PBS control) (Casalino-Matsuda et al., 2006).
Intranasal insitillation of 0.1 mg LPS (E.coli 0111:B4) once a day for 3 consecutive days induced goblet cell metaplasia in the nasal epithelium (as judged by histopathology), with an approx. 50% increase in AB/PAS-stained epithelium compared to untreated controls (Takezawa et al., 2016).
Induction of airway inflammation with 50 µg house dust mite (1.27 endotoxin units/mg) for 5 days/week for 6 weeks resulted goblet cell metaplasia as evidenced by extensive AB staining in the animals' airways (Le Cras et al., 2011). Using the same model with a 3-week treatment demonstrated goblet cell metaplasia as judged by increased PAS staining in the airway epithelium and ca. 10-, 5-, and 4-fold increases in expression of goblet cell metaplasia-related genes Muc5ac, Clca1, and Postn, respectively (Habibovic et al., 2016).
Pyocyanin, a redox-active exotoxin of Pseudomonas aeruginosa, caused goblet cell metaplasia in C57Bl/6 mice after 3-week treatment (25 µg/day). PAS staining increased by ca. 30%; the percentage of Muc5ab-positive cell in bronchial epithelium increased 6.4-fold and in bronchiolar epithelium 11.4-fold (Hao et al., 2012).
Male Sprague–Dawley rats that were exposed to 3 ppm acrolein for 6 h a day, for 12 days developed goblet cell metaplasia (as judged by histopathology), increasing the % AB/PAS-positive stained epithelium from ca. 5% (in air controls) to 35%. This was accompanied by a nearly 15% increase in Muc5ac-positive stained cells, a ca. 3-fold increase in Muc5ac mRNA expression and a ca. 4-fold increase in protein expression (Chen et al., 2010).
Exposure of female Sprague-Dawley rats to wood smoke (40 g of China fir sawdust was smoldered) for 1 h four times per day, five days per week, for three months caused goblet cell metaplasia in the airways (as judged by histopathology), a 2-fold increase in Muc5ac gene expression, an increase in the % AB/PAS-positive stained epithelium from approx. 6% (air controls) to ca. 17%, an increase in Muc5ac-positive stained cells from approx. 5% (air controls) to ca. 25% (Huang et al., 2017).
Exposure of male Sprague-Dawley rats to smoke from five cigarettes (2R4F, University of Kentucky) a day for 5 days resulted in goblet cell metaplasia in the airways (as judged by histopathology) and an approx. 70% increase in AB/PAS-stained epithelium (Lee et al., 2006).
Intratracheal instillation of LPS (P. aeruginosa serotype 10; 200 or 300 μg in 300 μL PBS) in male Sprague-Dawley rats caused goblet cell metaplasia in the airways, with 42.31 ± 3.36, 45.46 ± 2.24, and 63.13 ± 4.6% AB/PAS-positive staining at 3, 5, and 7 days after low-dose LPS instillation, respectively, and 71.6 ± 2.56% AB/PAS-positive staining at 7 days after high-dose LPS instillation. MUC5AC protein expression in the bronchial epithelium of the control and LPS groups (300 μg, 7 days post-instillation) were 5.46 ± 4.68 and 75.32 ± 4.53, respectively (Kim et al., 2004).
Time-scale
Instillation of agarose plugs (0.7-0.8 mm diameter, 4% agarose II) in Fischer rats caused a time-dependent increase in goblet cell area (by AB/PAS staining), which was detectable as early as 24 h and was greatest 72 h post-instillation. The AB/PAS-stained area increased from 0.1 ± 0.1% in control animals to 4.7 ± 1.4, 13.3 ± 0.7, and to 19.1 ± 0.7% at 24, 48, and 72 h post-instillation, respectively. Goblet cell numbers increased from 0 to 13.1 ± 5.6, 25.7 ± 15.0, and 51.5 ± 9.0 cells/mm basal lamina at 24, 48, and 72 h post-instillation, respectively (Lee et al., 2000).
Intratracheal instillation of LPS (P. aeruginosa serotype 10; 200 or 300 μg in 300 μL PBS) in male Sprague-Dawley rats caused goblet cell metaplasia in the airways, with 42.31 ± 3.36, 45.46 ± 2.24, and 63.13 ± 4.6% AB/PAS-positive staining at 3, 5, and 7 days after low-dose LPS instillation, respectively, and 71.6 ± 2.56% AB/PAS-positive staining at 7 days after high-dose LPS instillation. MUC5AC protein expression in the bronchial epithelium of the control and LPS groups (300 μg, 7 days post-instillation) were 5.46 ± 4.68 and 75.32 ± 4.53, respectively (Kim et al., 2004).
Known Feedforward/Feedback loops influencing this KER
Unknown