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Event: 919

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Occurrence, Transdifferentiation of ciliated epithelial 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. The short name should be less than 80 characters in length. More help
Occurrence, Transdifferentiation of ciliated epithelial cells

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help
Level of Biological Organization
Cellular

Cell term

Further information on Event Components and Biological Context may be viewed on the attached pdf.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. More help
Cell term
ciliated epithelial cell

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.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. More help
Organ term
lung

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). 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 signalling 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. More help
Process Object Action
transdifferentiation ciliated epithelial 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

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. 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 Low NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help
Life stage Evidence
Adult Moderate

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
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. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

Transdifferentiation is defined as the conversion of one cell type to another (Shen et al., 2004). Transdifferentiation of ciliated epithelial cells into goblet cells results in goblet cell metaplasia and, as a consequence, mucus hypersecretion.

Airway epithelial injury can be caused by various inhalation exposures (e.g. cigarette smoke, sulphur dioxide, endotoxin, viruses). Subsequent tissue repair processes are thought to initiate the transdifferentiation process, whereby ciliated epithelial cells first dedifferentiate and then redifferentiate to goblet cells, without an apparent increase in the total number of epithelial cells (Lumsden et al., 1984; Shimizu et al., 1996; Reader et al., 2003).

Alternatively, transdifferentiation may occur following the activation of EGFR-mediated anti-apoptotic signaling in ciliated epithelial cells. Subsequent stimulation by proinflammatory stimuli such as the Th2 cytokines interleukin (IL)-4 and IL-13 then promotes transdifferentiation of ciliated cells into goblet cells, thereby increasing the number of goblet cells (“second hit hypothesis”) in mouse tracheal epithelium and airway epithelia of COPD patients (Laoukili et al., 2001; Tyner et al., 2006; Curran and Cohn, 2010).

Current knowledge pertaining to how inhibition of ciliated cell apoptosis leads to transdifferentiation that eventually contributes to an increase in goblet cell numbers is still incomplete. The available evidence for this KE is indirect or correlative (Tyner et al., 2006; Silva et al., 2012; Reader et al., 2003; Turner et al., 2011; Ayers et al., 1988; Jefferey et al., 1984). It also is not in agreement with other studies, which show that ciliated cells do not give rise to goblet cells during airway remodeling in rodents and humans, and with studies that provide evidence for increased goblet cell proliferation (Lumsden et al., 1984; Casalino-Matsuda et al., 2006; Hays et al., 2006; Tesfaigzi et al., 2004; Taniguchi et al., 2011).

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. 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).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

Ciliated epithelial cells are characterized by cilia beating, apical localization of ezrin and basal bodies, and expression of Foxj1 and glutamylated tubulin (Laoukili et al., 2001; Gomperts et al., 2007). Ciliated epithelial cells may be detected by light or electron microscopy, although the latter is typically used for ultrastructural evaluation rather than enumeration of this cell type. Instead, immunocytochemical labelling with anti-tubulin or anti-Foxj1 antibodies is frequently employed to establish ciliated epithelial cell count on histological sections of tissues; flow cytometric analysis also appears to be used rather infrequently for this purpose.

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. Alternatively, staining of tissue sections with Alcian blue (AB) or AB in combination with periodic acid–Schiff (PAS) can be used to highlight and count mucus-containing goblet cells.

Transdifferentiation in the airway epithelium is difficult to quantify. In live animals, lineage tracing studies in models of asthma or respiratory infection provided evidence that transdifferentiation occurs (Tyner et al., 2006; Gomperts et al., 2007; Turner et al., 2011). An experienced pathologist may assign a score that reflects the extent of airway remodeling in animal and human lung tissues, but no standard exists, and the results are at best semi-quantitative and study-specific. Some investigators view the appearance of cells bearing morphological characteristics of both ciliated and goblet cells, and co-localization of ciliated and goblet cell markers in situ, as sufficient evidence for transdifferentiation (Gomperts et al., 2007; Rogers, 1994).

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

There are a number of human studies demonstrating transdifferentiation from ciliated to goblet cells in 3D human airway epithelial models (Gomperts et al., 2007), human bronchial or nasal epithelial cells in vitro (Yoshisue and Hasegawa 2004, Turner et al., 2011, Laoukili et al., 2001) and in COPD patients (Tyner et al., 2006). Transdifferentiation and goblet metaplasia were also shown in mouse respiratory epithelia following IL-13 treatment (Tyner et al., 2006, Fujisawa et al., 2008), although another study found that ciliated cells do not become goblet cells after ovalbumin challenge (Pardo-Saganta et al., 2013). Instillation of IL-13 or sensitization with ovalbumin also resulted in goblet cell metaplasia in rats (Shim et al., 2001; Takeyama et al., 2008). However, to our knowledge, transdifferentiation of ciliated to goblet cells was not directly assessed in these studies.

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help
Ayers, M. M., Jeffery, P. K (1998). Proliferation and differentiation in mammalian airway epithelium. Eur. Resp. J. 1, 58-80.
 

Casalino-Matsuda, S. M., Monzón, M. E., & Forteza, R. M (2006). Epidermal growth factor receptor activation by epidermal growth factor mediates oxidant-induced goblet cell metaplasia in human airway epithelium. Am. J. Resp. Cell Mol. Biol. 34, 581-591.

Curran, D.R., and Cohn, L (2010). Advances in mucous cell metaplasia: a plug for mucus as a therapeutic focus in chronic airway disease. Am. J. Resp. Cell Mol. Biol. 42, 268-275.

Fujisawa, T., Ide, K., 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. Respirology 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. Resp. Cell Mol. Biol. 37, 339-346.

Hays, S.R., and Fahy, J.V. (2006). Characterizing mucous cell remodeling in cystic fibrosis: relationship to neutrophils. Am. J. Resp. Crit. Care Med. 174, 1018-1024.

Jefferey, P., Rogers, D., Ayers, M., and Shields, P. (1984). "Structural aspects of cigarette smoke-induced pulmonary disease". In Smoking and the Lung (Springer), pp. 1-31.

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.

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.

Pardo-Saganta, A., Law, B.M., Gonzalez-Celeiro, M., Vinarsky, V., and Rajagopal, J. (2013). Ciliated cells of pseudostratified airway epithelium do not become mucous cells after ovalbumin challenge. Am. J. Resp. Cell Mol. Biol. 48, 364-373.

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.

Rogers, D. (1994). Airway goblet cells: responsive and adaptable front-line defenders. Eur. Resp. J. 7, 1690-1706.

Shen, C.-N., Burke, Z.D., and Tosh, D. (2004). Transdifferentiation, metaplasia and tissue regeneration. Organogenesis 1, 36-44. 

Shim, J.J., Dabbagh, K., Ueki, I.F., Dao-Pick, T., Burgel, P.R., Takeyama, K., et al. (2001). IL-13 induces mucin production by stimulating epidermal growth factor receptors and by activating neutrophils. Am. J. Physiol. Lung Cell. Mol. Physiol. 280, L134-140.

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.

Taniguchi, K., Yamamoto, S., Aoki, S., Toda, S., Izuhara, K., and Hamasaki, Y. (2011). Epigen is induced during the interleukin-13–stimulated cell proliferation in murine primary airway epithelial cells. Exp. Lung Res. 37, 461-470.

Tesfaigzi, Y., Harris, J.F., Hotchkiss, J.A., and Harkema, J.R. (2004). DNA synthesis and Bcl-2 expression during development of mucous cell metaplasia in airway epithelium of rats exposed to LPS. Am. J. Physiol. Lung Cell. Mol. Physiol. 286, L268-L274.

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.

Yoshisue, H., and Hasegawa, K. (2004). Effect of MMP/ADAM inhibitors on goblet cell hyperplasia in cultured human bronchial epithelial cells. Biosci. Biotech. Biochem. 68(10), 2024-2031.