API

Event: 921

Key Event Title

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Occurrence, Hyperplasia of goblet cells

Short name

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Goblet cell hyperplasia

Key Event Component

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Process Object Action
hyperplasia goblet cell occurrence

Key Event Overview


AOPs Including This Key Event

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AOP Name Role of event in AOP
EGFR Activation Leading to Decreased Lung Function KeyEvent

Stressors

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Level of Biological Organization

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Biological Organization
Tissue


Organ term

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Organ term
lung


Taxonomic Applicability

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Term Scientific Term Evidence Link
human Homo sapiens Strong NCBI
mouse Mus musculus Strong NCBI
rat Rattus norvegicus Strong NCBI
ferret Mustela putorius furo Not Specified NCBI
guinea pig Cavia porcellus Strong NCBI

Life Stage Applicability

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Life stage Evidence
Adult Strong
3 to < 6 years Moderate
6 to < 11 years Moderate
11 to < 16 years Moderate

Sex Applicability

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Term Evidence
Mixed Strong

How This Key Event Works

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Goblet cell hyperplasia refers to the increase in goblet cell numbers and is as common feature of airway epithelia in asthma and other respiratory diseases. It can arise from sustained proliferation of this cell population following airway injury by, for example, exposure to allergens, pathogens, cigarette smoke and other inhalation exposures (Miyabara et al., 1998; Nagao et al., 2003; Saetta et al., 2000; van Hove et al., 2009; Walter et al., 2002; Hao et al., 2014; Lukacs et al., 2010; Hao et al., 2013; Yageta et al., 2014; Nie et al., 2012; Hegab et al., 2007; Kim et al., 2016).

Following EGFR activation, classical downstream activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, also known as Raf/Ras/MAPK/ERK pathway, increases airway epithelial cell proliferation (Lemjabbar et al., 2003; Kim et al., 2005; Hackel et al., 1999) and facilitates epithelial wound repair (Burgel & Nadel, 2004; Van Winkle et al., 1997; Allahverdian et al., 2010). While there is evidence that increased goblet cell proliferation may be the underlying cause of goblet cell hyperplasia (GCH; Silva et al., 2012), the key players mediating an increase in airway goblet cell numbers following EGFR activation are still largely unexplored. Basal epithelial cells which exhibit stem cell-like properties have been postulated to function as a source of goblet cells in injured airways, utilizing cell fate pathways that favor secretory cells over other cell populations (Rock et al., 2009).  However, both in vitro studies and studies in mouse models of asthma, COPD, and viral infection indicate that transdifferentiation of ciliated or club cells into goblet cells, which is referred to as goblet cell metaplasia (GCM), more likely contributes to the expansion of this cell population in the airways (Tyner et al., 2006; Lumsden et al., 1984; Reader et al., 2003; Turner et al., 2011; Evans et al., 2004; Lamb et al., 1968; Shimizu et al., 1998). Furthermore, such increases in the number of goblet cells are suppressed when EGFR activity is inhibited (Tyner et al., 2006).

 

 


How It Is Measured or Detected

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Goblet cells are mucin-producing columnar epithelial cells, and their secretory granules can be identified easily by light or electron microscopy (Rogers, 1994). However, MUC5AC immunohistochemical staining is typically used to identify and enumerate this cell type in tissue sections, even though this is semi-quantitative at best. Alternatively, staining of tissue sections with Alcian blue (AB) or AB in combination with periodic acid–Schiff (PAS) can also be used to highlight and count mucus-containing goblet cells. In addition, the simultaneous detection and quantification of proliferation markers such as PCNA or Ki-67 may prove helpful in identifying proliferating goblet cells following airway injury.

In laboratory animals, GCH may be idenitfied by a pathologist as an increase in the number of goblet cells in an epithelium which normally contains some goblet cells (Harkema and Hotchkiss, 1993). Similarly, a trained pathologist may assign a score for the extent of GCH occurring in human airway epithelial tissues, and although no standard for this assessment exists, this appears to be a clinically accepted approach.


Evidence Supporting Taxonomic Applicability

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Goblet cell hyperplasia was reported in respiratory epithelia of humans, mice and rats following various inhalation exposures (Saetta et al., 2000; Takeyama et al., 2008; Tesfaigzi et al., 2000; Werley et al., 2016). Although GCH is a common feature of adaptation to respiratory irritants and/or airway epithelial repair among these species, some species differences exist with respect to the sensitivity toward certain exposures (Wolf et al., 1995; NTP, 1994).

 


References

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Allahverdian, S., Wang, A., Singhera, G.K., Wong, B.W., and Dorscheid, D.R. (2010). Sialyl Lewis X modification of the epidermal growth factor receptor regulates receptor function during airway epithelial wound repair. Clinical & Experimental Allergy 40, 607-618.

Burgel, P., and Nadel, J. (2004). Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium. Thorax 59, 992-996.

Evans, C.M., Williams, O.W., Tuvim, M.J., Nigam, R., Mixides, G.P., Blackburn, M.R., DeMayo, F.J., Burns, A.R., Smith, C., Reynolds, S.D., et al. (2004). Mucin Is produced by Clara cells in the proximal airways of antigen-challenged mice. American Journal of Respiratory Cell and Molecular Biology 31, 382-394.

Hackel, P.O., Zwick, E., Prenzel, N., and Ullrich, A. (1999). Epidermal growth factor receptors: critical mediators of multiple receptor pathways. Current Opinion in Cell Biology 11, 184-189.

Hao, Y., Kuang, Z., Jing, J., Miao, J., Mei, L.Y., Lee, R.J., Kim, S., Choe, S., Krause, D.C., and Lau, G.W. (2014). Mycoplasma pneumoniae modulates STAT3-STAT6/EGFR-FOXA2 signaling to induce overexpression of airway mucins. Infection and Immunity 82, 5246-5255.

Hao, Y., Kuang, Z., Xu, Y., Walling, B.E., and Lau, G.W. (2013). Pyocyanin-induced mucin production is associated with redox modification of FOXA2. Respiratory Research 14, 82-82.

Harkema, J.R., and Hotchkiss, J.A. (1993). Ozone- and endotoxin-induced mucous cell metaplasias in rat airway epithelium: Novel animal models to study toxicant-induced epithelial transformation in airways. Toxicology Letters 68, 251-263.

Hegab, A.E., Sakamoto, T., Nomura, A., Ishii, Y., Morishima, Y., Iizuka, T., Kiwamoto, T., Matsuno, Y., Homma, S., and Sekizawa, K. (2007). Niflumic acid and AG-1478 reduce cigarette smoke-induced mucin synthesis: The role of hCLCA1. Chest 131, 1149-1156.

Kim, S., Schein, A.J., and Nadel, J.A. (2005). E-cadherin promotes EGFR-mediated cell differentiation and MUC5AC mucin expression in cultured human airway epithelial cells. American Journal of Physiology - Lung Cellular and Molecular Physiology 289, L1049-L1060.

Kim, B.-G., Lee, P.-H., Lee, S.-H., Kim, Y.-E., Shin, M.-Y., Kang, Y., Bae, S.-H., Kim, M.-J., Rhim, T., Park, C.-S., et al. (2016). Long-Term Effects of Diesel Exhaust Particles on Airway Inflammation and Remodeling in a Mouse Model. Allergy, Asthma & Immunology Research 8, 246-256.

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. Journal of Pathology and Bacteriology 96, 97-111.

Lemjabbar, H., Li, D., Gallup, M., Sidhu, S., Drori, E., and Basbaum, C. (2003). Tobacco smoke-induced lung cell proliferation mediated by tumor necrosis factor alpha-converting enzyme and amphiregulin. Journal of Biological Chemistry 278, 26202-26207.

Lukacs, N.W., Smit, J.J., Nunez, G., and Lindell, D.M. (2010). Respiratory Virus-induced TLR7 activation controls IL-17 associated Increase in mucus via IL-23 regulation: Respiratory virus induced immune environment relies on TLR7-mediated pathways to preserve a non-pathogenic response and regulates IL-17 production. Journal of immunology (Baltimore, Md : 1950) 185, 2231-2239.

Lumsden, A.B., McLean, A., and Lamb, D. (1984). Goblet and Clara cells of human distal airways: evidence for smoking induced changes in their numbers. Thorax 39, 844-849.

Miyabara, Y., Ichinose, T., Takano, H., Lim, H.-B., and Sagai, M. (1998). Effects of diesel exhaust on allergic airway inflammation in mice. Journal of allergy and clinical immunology 102, 805-812.

Nagao, K., Tanaka, H., Komai, M., Masuda, T., Narumiya, S., and Nagai, H. (2003). Role of Prostaglandin I2 in Airway Remodeling Induced by Repeated Allergen Challenge in Mice. American Journal of Respiratory Cell and Molecular Biology 29, 314-320.

Nie, Y.-C., Wu, H., Li, P.-B., Luo, Y.-L., Zhang, C.-C., Shen, J.-G., and Su, W.-W. (2012). Characteristic comparison of three rat models induced by cigarette smoke or combined with LPS: to establish a suitable model for study of airway mucus hypersecretion in chronic obstructive pulmonary disease. Pulmonary Pharmacology & Therapeutics 25, 349-356.

NTP (1994). NTP Toxicology and Carcinogenesis Studies of Ozone (CAS No. 10028-15-6) and Ozone/NNK (CAS No. 10028-15-6/64091-91-4) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). National Toxicology Program technical report series 440, 1.

Reader, J.R., Tepper, J.S., Schelegle, E.S., Aldrich, M.C., Putney, L.F., Pfeiffer, J.W., and Hyde, D.M. (2003). Pathogenesis of mucous cell metaplasia in a murine asthma model. American Journal of Pathology 162, 2069-2078.

Rock, J.R., Onaitis, M.W., Rawlins, E.L., Lu, Y., Clark, C.P., Xue, Y., Randell, S.H., and Hogan, B.L. (2009). Basal cells as stem cells of the mouse trachea and human airway epithelium. Proceedings of the National Academy of Sciences of the United States of America 106, 12771-12775.

Rogers, D. (1994). Airway goblet cells: responsive and adaptable front-line defenders. European Respiratory Journal 7, 1690-1706.

Saetta, M., Turato, G., Baraldo, S., Zanin, A., Braccioni, F., Mapp, C.E., Maestrelli, P., Cavallesco, G., Papi, A., and Fabri, L.M. (2000). Goblet Cell Hyperplasia and Epithelial Inflammation in Peripheral Airways of Smokers with Both Symptoms of Chronic Bronchitis and Chronic Airflow Limitation. American Journal of Respiratory and Critical Care Medicine 161, 1016-1021.

Shimizu, T., Takahashi, Y., Kawaguchi, S., and Sakakura, Y. (1996). Hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium induced by endotoxin. American Journal of Respiratory and Critical Care Medicine 153, 1412-1418.

Silva, M.A., and Bercik, P. (2012). Macrophages are related to goblet cell hyperplasia and induce MUC5B but not MUC5AC in human bronchus epithelial cells. Laboratory Investigation 92, 937-948.

Takeyama, K., Tamaoki, J., Kondo, M., Isono, K., and Nagai, A. (2008). Role of epidermal growth factor receptor in maintaining airway goblet cell hyperplasia in rats sensitized to allergen. Clinical & Experimental Allergy 38, 857-865.

Tesfaigzi, Y., Fischer, M.J., Martin, A.J., and Seagrave, J. (2000). Bcl-2 in LPS- and allergen-induced hyperplastic mucous cells in airway epithelia of Brown Norway rats. American Journal of Physiology - Lung Cellular and Molecular Physiology 279, L1210-L1217.

Turner, J., Roger, J., Fitau, J., Combe, D., Giddings, J., Heeke, G.V., and Jones, C.E. (2011). Goblet cells are derived from a FOXJ1-expressing progenitor in a human airway epithelium. American Journal of Respiratory Cell and Molecular Biology 44, 276-284.

Tyner, J.W., Kim, E.Y., Ide, K., Pelletier, M.R., Roswit, W.T., Morton, J.D., Battaile, J.T., Patel, A.C., Patterson, G.A., Castro, M., et al. (2006). Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-13 transdifferentiation signals. Journal of Clinical Investigation 116, 309-321.

Van Hove, C.L., Maes, T., Cataldo, D.D., Guéders, M.M., Palmans, E., Joos, G.F., and Tournoy, K.G. (2009). Comparison of acute inflammatory and chronic structural asthma-like responses between C57BL/6 and BALB/c mice. International archives of allergy and immunology 149, 195-207.

Van Winkle, L.S., Isaac, J.M., and Plopper, C.G. (1997). Distribution of epidermal growth factor receptor and ligands during bronchiolar epithelial repair from naphthalene-induced Clara cell injury in the mouse. American Journal of Pathology 151, 443.

Walter, M.J., Morton, J.D., Kajiwara, N., Agapov, E., and Holtzman, M.J. (2002). Viral induction of a chronic asthma phenotype and genetic segregation from the acute response. The Journal of Clinical Investigation 110, 165-175.

Werley, M.S., Kirkpatrick, D.J., Oldham, M.J., Jerome, A.M., Langston, T.B., Lilly, P.D., Smith, D.C., and McKinney, W.J. (2016). Toxicological assessment of a prototype e-cigaret device and three flavor formulations: a 90-day inhalation study in rats. Inhalation Toxicology 28, 22-38.

Wolf, D., Morgan, K., Gross, E., Barrow, C., Moss, O., James, R., and Popp, J. (1995). Two-year inhalation exposure of female and male B6C3F1 mice and F344 rats to chlorine gas induces lesions confined to the nose. Toxicological Sciences 24, 111-131.

Yageta, Y., Ishii, Y., Morishima, Y., Ano, S., Ohtsuka, S., Matsuyama, M., Takeuchi, K., Itoh, K., Yamamoto, M., and Hizawa, N. (2014). Carbocisteine reduces virus-induced pulmonary inflammation in mice exposed to cigarette smoke. American Journal of Respiratory Cell and Molecular Biology 50, 963-973.