Key Event Title
|Level of Biological Organization|
Key Event Components
|epithelial cell apoptotic process||decreased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Decreased lung function||KeyEvent|
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. Cell death assays range from simple cellular stains for use with platforms such as flow cytometers for detection of specific markers, e.g. caspase, to more sophisticated multiplex assays (Archana et al., 2013; Muppidi et al., 2004). 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 ciliated 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.
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.
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. Baltim. Md 1950 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., 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.