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Key Event Title
Decrease, Apoptosis of ciliated epithelial cells
|Level of Biological Organization|
|ciliated epithelial cell|
Key Event Components
|apoptotic process||ciliated epithelial cell||decreased|
Key Event Overview
AOPs Including This Key Event
Key Event Description
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
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
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).
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.
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.
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.
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.
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.