Relationship:962

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Key Event Relationship Overview

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Description of Relationship

Upstream Event Downstream Event/Outcome
EGFR, Activation Apoptosis of ciliated epithelial cells, Decrease

AOPs Referencing Relationship

AOP Name Type of Relationship Weight of Evidence Quantitative Understanding
EGFR Activation Leading to Decreased Lung Function Directly Leads to Moderate Weak

Taxonomic Applicability

Name Scientific Name Evidence Links
human Homo sapiens Moderate NCBI
mouse Mus musculus Moderate NCBI
rat Rattus norvegicus Moderate NCBI

How Does This Key Event Relationship Work

Ciliated cell apoptosis in lung epithelium is regulated by EGFR and PI3K, with their activation resulting in decreased apoptosis (Tyner et al., 2006).

Epithelial cell apoptosis is not driven by IL13 but instead by TGFA, as well as oxidative stress and is dependent on EGFR, JNK1/2, MEK and PI3K (Casalino-Matsuda et al., 2006), (Sydlik et al., 2006), (Takeyama et al., 2008).

Weight of Evidence

Biological Plausibility

Decrease in ciliated cell apoptosis due to EGFR has moderate biological plausibility. Blocking EGFR and PI3K in mouse trachea epithelial cells in air-liquid interface increased apoptosis shown by activation of caspase-3 and TUNEL-positive cells within 6 hours and was not regulated by IL13 (Tyner et al., 2006). This did not apply to MUC5AC-positive goblet cells and correlated with the decrease in ciliated cell number. Therefore it is moderately plausible that these non goblet cells undergoing apoptosis due to EGFR blockade were ciliated cells, considering that the mouse ciliated cells make up 45% of cells in in vitro culture.

Other studies looking generally at epithelial cell apoptosis, which presumably includes half ciliated cells, showed that xanthine oxidase induced BCL2 expression in human airway epithelial cells which was inhibited by catalase and anti-EGFR antibodies (Casalino-Matsuda et al., 2006), EGFR and JNK1/2 inhibition resulted in increased apoptosis measured by caspase-3 activation in rat lung epithelial cell line RLE-6TN treated with ultrafine particles (Sydlik et al., 2006) and TGFA-treated NCI-H292 cells increased BCL2 protein and EGFR inhibitor prevented BCL2 increase and induced apoptosis (Takeyama et al., 2008). The last two studies are in epithelial cell lines which do not contain differentiated ciliated cells.

Empirical Support for Linkage

Include consideration of temporal concordance here

Caspase-3 positive cells increased by four-fold and TUNEL+ cells increased by 3-fold with EGFR and PI3K inhibition in mouse tracheal epithelial cell cultures. Although these cells were shown to be non-goblet cells, they could also represent non-ciliated cells. A dose-dependent decrease in beta-tubulin cells with increasing EGFR and PI3K inhibitor dose correlates with the increase in apoptotic epithelial cells (Tyner et al., 2006). Studies have shown a decrease in ciliated cells (Gomperts et al. 2007) or ciliary beat frequency (Laoukili et al., 2001) with increased dose of IL13 or EGFR activation.

Because this relationship is not specifically proven to be causal and there are no studies looking at multiple KEs in response to a perturbation, the empirical support showing ciliated cell apoptosis is weak.

Uncertainties or Inconsistencies

Ciliated cell apoptosis due to EGFR inhibition has not been specifically studied. Decreased number in ciliated cells due to EGFR blockade correlated with increased apoptosis of non-goblet cells due to EGFR blockade, however it is possible that decreased ciliated cells could be due to necrosis or other non-apoptotic cell death pathways and that non-goblet cells could represent basal or Clara cells.

Quantitative Understanding of the Linkage

Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?

0.6 mM xanthine plus 0.05 units of xanthine oxidase (X/XO) for 3 days led to an increase in Bcl2 RNA which was blocked by catalase and EGFR antibodies (Casalino-Matsuda et al., 2006). 10ng/mL TGFA for 24 hours led to an increase in Bcl2 RNA blocked by EGFR and MEK inhibitors AG1478 or PD98059 and TGFA treatment with EGFR and PI3K inhibitors AG1478 and LY294002 induced apoptosis.

Evidence Supporting Taxonomic Applicability

The studies that support epithelial cell apoptosis induced by EGFR include rat, mouse and human in vitro experiments.

References

1. Casalino-Matsuda, S., Monzón, M., and Forteza, R. (2006). Epidermal Growth Factor Receptor Activation by Epidermal Growth Factor Mediates Oxidant-Induced Goblet Cell Metaplasia in Human Airway Epithelium. Am J Respir Cell Mol Biol 34, 581–591.

2. Curran, D., and Cohn, L. (2010). Advances in mucous cell metaplasia: a plug for mucus as a therapeutic focus in chronic airway disease. Am J Respir Cell Mol Biol 42, 268–275.

3. Sydlik, U., Bierhals, K., Soufi, M., Abel, J., Schins, R.P.F., and Unfried, K. (2006). Ultrafine carbon particles induce apoptosis and proliferation in rat lung epithelial cells via specific signaling pathways both using EGF-R. Am. J. Physiol. Lung Cell. Mol. Physiol. 291, L725–L733.

4. 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 J. Br. Soc. Allergy Clin. Immunol. 38, 857–865.

5. 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.