Key Event Overview
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AOPs Including This Key Event
|AOP Name||Event Type||Essentiality|
|EGFR Activation Leading to Decreased Lung Function||KE||Moderate|
Level of Biological Organization
How this Key Event works
Ciliated cell apoptosis in lung epithelium is regulated by EGFR and PI3K, with their activation resulting in decreased apoptosis (Tyner et al., 2006). This could contribute to transdifferentiation of ciliated cells into goblet cells. It has been proposed that ciliated cell transdifferentiation requires two signals – first EGFR leads to inhibition of apoptosis of ciliated cells, followed by their transition into goblet cells by IL13 (Curran and Cohn, 2010).
How it is Measured or Detected
Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?
Apoptosis of epithelial cells is shown by TUNEL-positive immunostaining, decrease in anti-apoptotic protein Bcl2 and increase in pro-apoptotic caspase-3 using immunoblotting and immunocytochemistry. To suggest ciliated cell apoptosis, decrease in beta-tubulin+ cells was correlated with increase in apoptosis of epithelial cells (Tyner et al., 2006).
Evidence Supporting Taxonomic 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 many studies in mouse, rat, human ((Monick et al., 2005), (Chimenti et al., 2007), (An et al., 2007), (Hart et al., 1999), (Matute-Bello et al., 1999), (Ravichandran et al., 2010), (Yang et al., 2013).
1. An, S., Hishikawa, Y., Liu, J., and Koji, T. (2007). Lung injury after ischemia-reperfusion of small intestine in rats involves apoptosis of type II alveolar epithelial cells mediated by TNF-alpha and activation of Bid pathway. Apoptosis Int. J. Program. Cell Death 12, 1989–2001.
2. Chimenti, L., Morici, G., Paternò, A., Bonanno, A., Siena, L., Licciardi, A., Veca, M., Guccione, W., Macaluso, F., Bonsignore, G., et al. (2007). Endurance Training Damages Small Airway Epithelium in Mice. Am. J. Respir. Crit. Care Med. 175, 442–449.
3. 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.
4. Martínez-Girón, R., and Martínez-Torre, S. (2011). Apoptotic ciliated cells on sputum smear. Diagn. Cytopathol. 39, 941–942.
5. 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.
6. 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.
7. Ravichandran, P., Baluchamy, S., Sadanandan, B., Gopikrishnan, R., Biradar, S., Ramesh, V., Hall, J.C., and Ramesh, G.T. (2010). Multiwalled carbon nanotubes activate NF-κB and AP-1 signaling pathways to induce apoptosis in rat lung epithelial cells. Apoptosis Int. J. Program. Cell Death 15, 1507–1516.
8. 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.
9. 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.