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Event: 914

Key Event Title

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

Decrease, Apoptosis of ciliated epithelial cells

Short name

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Decreased ciliated cell apoptosis

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Biological Context

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Level of Biological Organization
Cellular

Cell 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

Cell term
ciliated epithelial cell

Organ term

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
apoptotic process	ciliated epithelial cell	decreased

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

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	Moderate	NCBI
mouse	Mus musculus	Moderate	NCBI
rat	Rattus norvegicus	Moderate	NCBI

Life Stages

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

Life stage	Evidence
Adult	Moderate

Sex Applicability

An indication of the the relevant sex for this KE. 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. More help

Apoptosis, a main form of programmed cell death, is an essential part of tissue homeostasis during all life stages. Under normal conditions, apoptosis for example serves to eliminate damaged or infected cells and enable wound repair and resolution of inflammation (Elmore, 2007). In the airways, apoptosis occurs following exposure to cigarette smoke (Mebratu et al., 2011, Ning et al., 2013; Valencia-Gattas et al., 2016), hydrogen peroxide (Goldkorn et al., 1998), ozone (Triantaphyllopoulos et al., 2011); endotoxin (Tesfaigzi et al., 2000); infectious agents (Rajan et al., 2000; Monick et al., 2005) and ovalbumin sensitization (Truong-Tran et al., 2002; Reader et al., 2003; Takeyama et al., 2008; Liu et al., 2017). Ciliated cell apoptosis in lung epithelium is regulated by EGFR and PI3K, with both their activation resulting in decreased apoptosis (Tyner et al., 2006).

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

Numerous apoptosis assays exist. They typically are based on the analysis of the characteristic features an apoptotic cell exhibits. For example, decreased DNA content, nuclear condensation and other morphological changes can be detected by flow cytometry (sub-G1 DNA content), Trypan Blue, or Hoechst staining. Electrophoresis or TUNEL assay can be used to determine the extent of DNA fragmentation. Annexin V staining can be used to confirm redistribution of phosphatidylserine from the inner plasma membrane to the extracellular surface. Additional propidium iodide staining would allow for a distinction between early and late apoptotic events. In addition, activation of caspases can be examined by caspase activity assays, and cytochrome c release from mitochondria during the early stages of apoptosis can be measured by ELISA. Finally, taking into consideration that the ratio between anti-apoptotic and pro-apoptotic proteins determines whether a cell lives or dies, examining the levels of BAX, BID, BAK, BIK, or BAD (pro-apoptotic) and Bcl-Xl and Bcl-2 (anti-apoptotic) by western blot and image analysis may also give an insight into cell fate (Bossy-Wetzel and Green, 2000; Oancea et al., 2006; Archana et al., 2013; Muppidi et al., 2004; Huerta et al., 2007; Loo, 2011; Kale et al., 2018). Inclusion of appropriate controls allows for quantitation of surviving or proliferating cell populations, as well as the extent and mode of cell death.

To support cell death in a specific subpopulation of the airway epithelium such as in ciliated epithelial cells would require identifying the cell type of interest first. This could be achieved by either staining the cell with a population-specific marker in situ, or by enriching the population of interest prior to monitoring cell proliferation and death. To the best of our knowledge, to date, only the double immunohistochemical/immunofluorescent staining of airway epithelial samples has been employed to demonstrate increased proliferation of goblet cells and decreased apoptosis of goblet or ciliated cells (Tyner et al., 2006; Takeyama et al., 2001; Tesfaigzi et al., 2004).

Domain of Applicability

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

Ciliated cell apoptosis has been shown in a few mouse and human studies (Tyner et al., 2006; Martínez-Girón and Martínez-Torre, 2011). Epithelial cell apoptosis (presumably including ciliated cells) has been shown in numerous studies in mouse, rat, human (Monick et al., 2005; Hart et al., 1999; Matute-Bello et al., 1999; Rajan et al., 2000; Reader et al., 2003; Triantaphyllopoulos et al., 2011; Ning et al., 2013; Valencia-Gattas et al., 2016; Yang et al., 2013; Liu et al., 2017).

References

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

Archana, M., Yogesh, T. L., & Kumaraswamy, K. L. (2013). Various methods available for detection of apoptotic cells-A review. Indian J. Cancer 50, 274.

Bossy-Wetzel, E., and Green, D.R. (2000). Assays for cytochrome c release from mitochondria during apoptosis. Methods Enzymol. 322, 235-242.

Elmore, S. (2007). Apoptosis: A Review of Programmed Cell Death. Toxicol. Pathol. 35, 495–516.

Goldkorn, T., Balaban, N., Matsukuma, K., Chea, V., Gould, R., Last, J., Chan, C., and Chavez, C. (1998). EGF-receptor phosphorylation and signaling are targeted by H2O2 redox stress. Am. J. Resp. Cell. Mol. Biol. 19, 786-798.

Hart, B.A., Lee, C.H., Shukla, G.S., Shukla, A., Osier, M., Eneman, J.D., and Chiu, J.F. (1999). Characterization of cadmium-induced apoptosis in rat lung epithelial cells: evidence for the participation of oxidant stress. Toxicology 133, 43–58.

Huerta, S., Goulet, E.J., Huerta-Yepez, S., and Livingston, E.H. (2007). Screening and detection of apoptosis. J. Surg. Res. 139, 143-156.

Kale, J., Osterlund, E.J., and Andrews, D.W. (2018). BCL-2 family proteins: changing partners in the dance towards death. Cell Death Differ. 25, 65-80.

Liu, Y., Pu, Y., Li, D., Zhou, L., & Wan, L. (2017). Azithromycin ameliorates airway remodeling via inhibiting airway epithelium apoptosis. Life Sci. 170, 1-8.

Loo, D.T. (2011). In situ detection of apoptosis by the TUNEL assay: an overview of techniques. Methods Mol. Biol. 682, 3-13.

Martínez-Girón, R., and Martínez-Torre, S. (2011). Apoptotic ciliated cells on sputum smear. Diagn. Cytopathol. 39, 941–942.

Matute-Bello, G., Liles, W.C., Steinberg, K.P., Kiener, P.A., Mongovin, S., Chi, E.Y., Jonas, M., and Martin, T.R. (1999). Soluble Fas ligand induces epithelial cell apoptosis in humans with acute lung injury (ARDS). J. Immunol. 163, 2217–2225.

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. Resp. Crit. Care Med. 183, 1531-1538.

Monick, M.M., Cameron, K., Staber, J., Powers, L.S., Yarovinsky, T.O., Koland, J.G., and Hunninghake, G.W. (2005). Activation of the Epidermal Growth Factor Receptor by Respiratory Syncytial Virus Results in Increased Inflammation and Delayed Apoptosis. J. Biol. Chem. 280, 2147–2158.

Muppidi, J., Porter, M., and Siegel, R.M. (2004). Measurement of apoptosis and other forms of cell death. Curr. Protoc. Immunol. 59, 3-17.

Ning, Y., Shang, Y., Huang, H., Zhang, J., Dong, Y., Xu, W., & Li, Q. (2013). Attenuation of cigarette smoke-induced airway mucus production by hydrogen-rich saline in rats. PLoS One 8, e83429.

Oancea, M., Mazumder, S., Crosby, M.E., and Almasan, A. (2006). Apoptosis assays. Methods Mol. Med. 129, 279-290.

Rajan, S., Cacalano, G., Bryan, R., Ratner, A. J., Sontich, C. U., van Heerckeren, A., et al. (2000). Pseudomonas aeruginosa induction of apoptosis in respiratory epithelial cells: analysis of the effects of cystic fibrosis transmembrane conductance regulator dysfunction and bacterial virulence factors. Am. J. Resp. Cell. Mol. Biol. 23, 304-312.

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.

Takeyama, K., Fahy, J., and Nadel, J. (2001). Relationship of epidermal growth factor receptors to goblet cell production in human bronchi. Am. J. Respir. Crit. Care Med. 163, 511-516.

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.

Triantaphyllopoulos, K., Hussain, F., Pinart, M., Zhang, M., Li, F., Adcock, I., et al. (2011). A model of chronic inflammation and pulmonary emphysema after multiple ozone exposures in mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 300, L691-L700.

Truong-Tran, A. Q., Ruffin, R. E., Foster, P. S., Koskinen, A. M., Coyle, P., Philcox, J. C., et al. (2002). Altered zinc homeostasis and caspase-3 activity in murine allergic airway inflammation. Am. J. Resp. Cell. Mol. Biol. 27, 286-296.

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.

Valencia-Gattas M, Conner GE, Fregien NL (2016). Gefitinib, an EGFR Tyrosine Kinase inhibitor, Prevents Smoke-Mediated Ciliated Airway Epithelial Cell Loss and Promotes Their Recovery. Ahmad S, ed. PLoS ONE 11, e0160216.

Yang, Y.-X., Li, X.-L., Wang, L., Han, S.-Y., Zhang, Y.-R., Pratheeshkumar, P., Wang, X., Lu, J., Yin, Y.-Q., Sun, L.-J., et al. (2013). Anti-apoptotic proteins and catalase-dependent apoptosis resistance in nickel chloride-transformed human lung epithelial cells. Int. J. Oncol. 43, 936–946.