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Event: 920

Key Event Title

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

Occurrence, Metaplasia 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 metaplasia
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Biological Context

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Level of Biological Organization

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

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; 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
Metaplasia goblet cell occurrence

Key Event Overview

AOPs Including This Key Event

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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 Moderate NCBI
rat Rattus norvegicus Moderate NCBI

Life Stages

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Life stage Evidence
Adult Moderate

Sex Applicability

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Term Evidence
Mixed Moderate

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

Metaplasia is the replacement of a differentiated cell type with another differentiated cell type. In the case of goblet cell metaplasia, ciliated or club cells transdifferentiate into goblet cells (Tyner et al., 2006; Evans et al., 2004), leading to an increased number of mucus-producing cells and eventually mucus hypersecretion. This adaptive change in the small airway epithelium, where goblet cells are typically sparse, is often observed following exposure to respiratory irritants including ozone, endotoxin and cigarette smoke (Harkema and Hotchkiss, 1993; Harkema and Wagner, 2002; Mebratu et al., 2011).

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

In vitro and in vivo studies assess metaplasia by looking for co-expression of cell markers or characteristics of two cell types though to be goblet cell progenitors, i.e. the club cell and the ciliated cell. CC-10/CSSP is commonly used as a club cell marker (Reader et al., 2003; Hayashi et al., 2004; Evans et al., 2004), while FOXJ1, beta-tubulin, tektin and DNAH9 were used as ciliated markers (Yoshisue and Hasegawa, 2004; Gomperts et al. 2007; Turner et al., 2011; Fujisawa et al., 2008). Apical localization of ezrin, ciliary beat frequency and glutamylated tubulins are other characteristics of ciliated cells (Laoukili et al., 2001). Transdifferentiation and metaplasia are said to occur when these ciliated cell characteristics and markers decrease, while expression of goblet cell markers such as MUC5AC and other mucin proteins increases. Light or fluorescence microscopy is used to show co-expression of markers and a transitory cell type (observation of goblet and cilia cell features within the same cell) (Tyner et al., 2006; Laoukili et al., 2001; Gomperts et al., 2007).

Goblet cell metaplasia is characterized by the presence of goblet cells (above the normal number; see above) in the epithelium lining the bronchi or bronchioles (Renne et al., 2009). In clinical samples, a pathologist may determine absence/presence of metaplasia. This assessment is not standardized, but based on experience, and may be semiquantitative if a score is assigned in relation to the extent of the finding.

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 metaplasia has been observed in human (Gomperts et al. 2007; Laoukili et al., 2001; Yoshisue and Hasegawa, 2004; Turner et al., 2011; Casalino-Matsuda et al., 2006) and in mouse lungs (Fujisawa et al., 2008; Tyner et al., 2006). Studies in rat have not directly measured transdifferentiation of ciliated to goblet cells. However, airway remodeling of small airway epithelium with nearly no goblet cells to an epithelium with numerous goblet cells was observed (Harkema and Hotchkiss, 1993).


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

Baginski, T.K., Dabbagh, K., Satjawatcharaphong, C., and Swinney, D.C. (2006). Cigarette smoke synergistically enhances respiratory mucin induction by proinflammatory stimuli. Am. J. Respir. Cell Mol. Biol. 35, 165-174.

Casalino-Matsuda, S., Monzón, M., and Forteza, R. (2006). Epidermal Growth Factor Receptor Activation by Epidermal Growth Factor Mediates Oxidant-Induced Goblet Cell Metaplasia in Human Airway Epithelium. Am. J. Respir. Cell Mol. Biol. 34, 581–591.

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. Respir. Cell Mol. Biol. 31, 382–394.

Fujisawa, T., Ide, K., Holtzman, M.J., Suda, T., Suzuki, K., Kuroishi, S., Chida, K., and Nakamura, H. (2008). Involvement of the p38 MAPK pathway in IL-13-induced mucous cell metaplasia in mouse tracheal epithelial cells. Respirol. 13, 191–202.

Gomperts, B.N., Kim, L.J., Flaherty, S.A., and Hackett, B.P. (2007). IL-13 regulates cilia loss and foxj1 expression in human airway epithelium. Am. J. Respir. Cell Mol. Biol. 37, 339-346. 

Harkema, J., and Hotchkiss, J. (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.

Harkema, J., and Wagner, J. (2002). Non-allergic models of mucous cell metaplasia and mucus hypersecretion in rat nasal and pulmonary airways. Novartis Found. Symp. 248, 181–197; discussion 197–200, 277–282.

Hayashi, T., Ishii, A., Nakai, S., and Hasegawa, K. (2004). Ultrastructure of goblet-cell metaplasia from Clara cell in the allergic asthmatic airway inflammation in a mouse model of asthma in vivo. Virchows Arch. Int. J. Pathol. 444, 66–73.

Jun, X., Ke, W., Feng, Y.-l., Chen, X.-r., Dan, X., and Zhang, M.-k. (2011). Role of extracellular signal-regulated kinase 1/2 in cigarette smoke-induced mucus hypersecretion in a rat model. Chin. Med. J. 124, 3327-3333.

Laoukili, J., Perret, E., Willems, T., Minty, A., Parthoens, E., Houcine, O., Coste, A., Jorissen, M., Marano, F., Caput, D., et al. (2001). IL-13 alters mucociliary differentiation and ciliary beating of human respiratory epithelial cells. J. Clin. Invest. 108, 1817–1824.

Larsen, S.r.T., Matsubara, S., McConville, G., Poulsen, S.S., and Gelfand, E.W. (2010). Ozone increases airway hyperreactivity and mucus hyperproduction in mice previously exposed to allergen. J. Toxicol. Environm. Health A 73, 738-747.

Liu, D.-S., Wang, T., Han, S.-X., Dong, J.-J., Liao, Z.-L., He, G.-M., et al. (2009). p38 MAPK and MMP-9 cooperatively regulate mucus overproduction in mice exposed to acrolein fog. Int. Immunopharmacol. 9, 1228-1235.

Mebratu, Y.A., Schwalm, K., Smith, K.R., Schuyler, M., and Tesfaigzi, Y. (2011). Cigarette Smoke Suppresses Bik To Cause Epithelial Cell Hyperplasia and Mucous Cell Metaplasia. Am. J. Respir. Crit. Care Med. 183, 1531-1538. 

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.

Renne, R., Brix, A., Harkema, J., Herbert, R., Kittel, B., Lewis, D., et al. (2009). Proliferative and nonproliferative lesions of the rat and mouse respiratory tract. Toxicol. Pathol. 37, Suppl. 7, 5s-73s. 

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. Respir. Cell Mol. Biol. 44, 276–284.

Tyner, J., Tyner, E., Ide, K., Pelletier, M., Roswit, W., Morton, J., Battaile, J., Patel, A., Patterson, G., 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.

Wagner, J.G., Van Dyken, S.J., Wierenga, J.R., Hotchkiss, J.A., and Harkema, J.R. (2003). Ozone exposure enhances endotoxin-induced mucous cell metaplasia in rat pulmonary airways. Toxicol. Sci. 74, 437-446.

Wang, T., Liu, Y., Chen, L., Wang, X., Hu, X.-R., Feng, Y.-L., et al. (2009). Effect of sildenafil on acrolein-induced airway inflammation and mucus production in rats. Eur. Resp. J. 33, 1122-1132.

Yoshisue, H., and Hasegawa, K. (2004). Effect of MMP/ADAM inhibitors on goblet cell hyperplasia in cultured human bronchial epithelial cells. Biosci. Biotechnol. Biochem. 68, 2024–2031.