Goblet cell metaplasia leads to Chronic, Mucus hypersecretion

This KER is inferred. However, that an increase in goblet cell numbers also increases mucin production is highly plausible. Studies in human cells, mice and rats demonstrate that mucin content or MUC5AC mRNA and protein expression increase in the presence of histologically confirmed goblet cell metaplasia. Because both events are measured in parallel and causal evidence is missing, our confidence is moderate.    

Goblet cell metaplasia and chronic mucus hypersecretion can be induced by a variety of insults including cigarette smoke, acrolein, bacterial products, neutrophil elastase, ozone and allergens.

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).  

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).  

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).  

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