Upstream eventDecrease, Apoptosis of ciliated epithelial cells
Occurrence, Transdifferentiation of ciliated epithelial cells
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|EGFR Activation Leading to Decreased Lung Function||adjacent||Moderate||Low|
Life Stage Applicability
Key Event Relationship Description
Downstream of EGFR activation, phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling elicits an anti-apoptotic response in ciliated cells, favoring their survival (Tyner et al., 2006). 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”) (Curran and Cohn, 2010).
Evidence Supporting this KER
There is no direct evidence linking decreased apoptosis in ciliated cells to their transdifferentiation. Co-localization of EGFR and β-tubulin but not CCSP or MUC5AC expression was observed in mouse airways 21 days after inoculation with Sendai virus and in the airways of asthma patients (Tyner et al., 2006; Takeyama et al., 2001). In addition, ciliated cell tagging studies in vitro indicated that the number of ciliated cells decreases following treatment with IL-13, while the number of goblet cells increases (Turner et al., 2011). Together these studies are supportive of transdifferentiation of ciliated into goblet cells.
While the evidence linking decreased apoptosis in ciliated cells to their transdifferentiation is indirect or correlative (Tyner et al., 2006; Silva and Bercik, 2012; Reader et al., 2003; Turner et al., 2011; Ayers et al., 1988; Jefferey et al., 1984), decreased ciliated cell apoptosis following exposure may imply that a (numerically stable) pool of cells is available for IL-13- and/or IL-4-mediated transdifferentiation to goblet cells (Curran and Cohn, 2010). Therefore, this KER is biologically plausible.
There is no direct evidence linking decreased apoptosis in ciliated cells to their transdifferentiation. Co-localization of EGFR and β-tubulin but not CCSP or MUC5AC expression was observed in Sendai virus-infected mouse airways and in the airways of asthma patients (Tyner et al., 2006; Takeyama et al., 2001). In addition, ciliated cell tagging studies in vitro indicated that the number of ciliated cells decreases following treatment with IL-13, while the number of goblet cells increases (Turner et al., 2011). Together these studies are supportive of ciliated cells transdifferentiating into goblet cells.
Uncertainties and Inconsistencies
Experimental evidence in support of this KER 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., 2001).
Quantitative Understanding of the Linkage
There is no quantitative understanding of the linkage as it has not been specifically studied.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The studies that support epithelial cell apoptosis induced by EGFR include rat, mouse and human in vitro experiments.
Ayers, M., and Jeffery, P. (1988). Proliferation and differentiation in mammalian airway epithelium. Eur Resp J 1, 58-80.
Casalino-Matsuda, S.M., Monzón, M.E., and 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.
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.
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.
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.
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., Fahy, J., and Nadel, J. (2001). Relationship of epidermal growth factor receptors to goblet cell production in human bronchi. Am J Resp Crit Care Med 163, 511-516.
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.