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Event: 921

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Occurrence, Hyperplasia of goblet cells

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Goblet cell hyperplasia
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Biological Context

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Level of Biological Organization
Tissue

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Organ term
lung

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
hyperplasia goblet cell occurrence

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Decreased lung function KeyEvent Karsta Luettich (send email) Under development: Not open for comment. Do not cite Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
mouse Mus musculus High NCBI
rat Rattus norvegicus High NCBI
ferret Mustela putorius furo Low NCBI
guinea pig Cavia porcellus High NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
Adult High

Sex Applicability

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Term Evidence
Mixed High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Goblet cell hyperplasia refers to an increase in goblet cell numbers and is a 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).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

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 identified by a pathologist as an increase in the number of goblet cells in an epithelium which normally contains only few goblet cells (Harkema and Hotchkiss, 1993). An experienced 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.

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

Goblet cell hyperplasia (GCH) was reported in respiratory epithelia of humans, mice, rats, ferrets and dogs following various inhalation exposures (Park et al.,1977; 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

List of the literature that was cited for this KE description. More help

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. Clin Exp 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. Am J Resp Cell Mol Biol 31, 382-394.

Hackel, P.O., Zwick, E., Prenzel, N., and Ullrich, A. (1999). Epidermal growth factor receptors: critical mediators of multiple receptor pathways. Curr Opin Cell Biol 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. Infect Immun 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. Respir Res 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. Toxicol Lett 68, 251-263.

Haswell, L.E., Hewitt, K., Thorne, D., Richter, A., and Gaça, M.D. (2010). Cigarette smoke total particulate matter increases mucous secreting cell numbers in vitro: A potential model of goblet cell hyperplasia. Toxicol. in Vitro 24, 981-987. 

Haswell, L.E., Smart, D., Jaunky, T., Baxter, A., Santopietro, S., Meredith, S., et al. (2021). The development of an in vitro 3D model of goblet cell hyperplasia using MUC5AC expression and repeated whole aerosol exposures. Toxicol. Lett. 347, 45-57. 

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.

Jang, A.-S., Choi, I.-S., Lee, J.-H., Park, C.-S., and Park, C.-S. (2006). Prolonged ozone exposure in an allergic airway disease model: adaptation of airway responsiveness and airway remodeling. Respir. Res. 7, 1-8.

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. Am J Physiol Lung Cell Mol Physiol 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 Immunol Res 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. J Pathol Bacteriol 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. J Biol Chem 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. J Immunol 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. J Allergy Clin Immunol 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. Am J Resp Cell Mol Biol 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. Pulm Pharmacol Ther 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.

Park, S.S., Kikkawa, Y., Goldring, I.P., Daly, M.M., Zelefsky, M., Shim, C., et al. (1977). An animal model of cigarette smoking in beagle dogs: correlative evaluation of effects on pulmonary function, defense, and morphology. Am. Rev. Respir. Dis. 115, 971-979.

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. Am J Pathol 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. PNAS 106, 12771-12775.

Rogers, D. (1994). Airway goblet cells: responsive and adaptable front-line defenders. Eur Respir J 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. Am J Resp Crit Care Med 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. Am J Resp Crit Care Med 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. Lab Invest 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. Clin Exp 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. Am J Physiol Lung Cell Mol Physiol 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. Am J Resp Cell Mol Biol 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. J Clin Invest 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. Int Arch Allergy Immunol 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. Am J Pathol 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. J Clin Invest 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. Inhal Toxicol 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. Toxicol Sci 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. Am J Resp Cell Mol Biol 50, 963-973.