Relationship:965

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Key Event Relationship Overview

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Description of Relationship

Upstream Event Downstream Event/Outcome
EGFR, Activation Transdifferentiation of ciliated epithelial cells, Increase

AOPs Referencing Relationship

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

Taxonomic Applicability

Name Scientific Name Evidence Links
mouse Mus musculus Moderate NCBI
human Homo sapiens Strong NCBI
rat Rattus norvegicus Weak NCBI
guinea pig Cavia porcellus Weak NCBI

How Does This Key Event Relationship Work

EGFR can be activated by IL13 and ROS to lead to ciliated cell transdifferentiation. IL13 stimulates transdifferentiation of ciliated epithelial cells to goblet cells through EGFR activation (Tyner et al., 2006), MMP/ADAM (Yoshisue and Hasegawa 2004), p38 MAPK (Fujisawa et al., 2008) and inhibition of FOXJ1 (Gomperts et al., 2007). In addition to IL13, IL4 has been shown to act through shared receptor IL4RA to stimulate goblet cell differentiation and inhibit ciliogenesis (Laoukili et al., 2001). IL4 and IL13 but not IL5 or IL9 have been shown to induce goblet cell metaplasia in mouse trachial epiethelial cells (Fujisawa et al., 2008). IL13 can activate EGFR by shedding EGFR ligand TGFA (Yoshisue and Hasegawa, 2004) and also act through IL4RA (Laoukili et al., 2001) and IL13RA2 (Tyner et al., 2006) which could be EGFR independent. EGFR can also be activated by xanthanine oxidase ROS via hyaluronic acid depolymerization and EGFR processing by tissue kalikrein which releases EGF (Casalino-Matsuda et al., 2006).

Weight of Evidence

Biological Plausibility

Two studies have shown EGFR involvement in a decrease in goblet cell and increase in ciliated cell numbers or marker expression via IL13 coinciding with increased TGFA (Yoshisue and Hasegawa, 2004) or ROS-induced EGFR ligand release (Casalino-Matsuda et al., 2006). A number of studies have shown ciliated cell transdifferentiation in response to IL13 in a mouse viral infection model and cultured mouse tracheal epithelial cells (Tyner et al., 2006), human nasal epithelial cells (Laoukili et al., 2001), a 3D human airway epithelial model (Gomperts et al., 2007) and human bronchial epithelial cells (Turner et al., 2011). IL13 could be acting through EGFR, however it is possible that it could be acting through EGFR-independent pathways.

It is not well-known how ciliated cell transdifferentiation occurs in humans. Under normal conditions, lung epithelial cells (except basal cells) are terminally differentiated, including ciliated cells (Rawlins and Hogan, 2008), and also in response to napthalene or sulfur dioxide-induced injury (Rawlins et al., 2006). However other studies showed that napthalene-induced injury can result in transdifferentiation of ciliated cells (Park et al., 2006).

Empirical Support for Linkage

Include consideration of temporal concordance here

One study has shown both an increase in goblet cells and decrease in ciliated cells and this is thought to be indicative of transdifferentiation (Turner 2011). In cultured human bronchial epithelial cells, goblet cells were derived from ciliated cells after 1 ng/mL IL13 treatment.

Since there is only one study showing the inverse relationship between goblet and ciliated cells numbers indicating transdifferentiation, the empirical support for this KER is moderate.

Uncertainties or Inconsistencies

IL13-induced goblet cell increase has been shown to be concentration-dependent in human bronchial epithelial cells with 1ng/ml inducing and 10ng/ml suppressing goblet cell increase (Atherton, et al. 2003), however multiple studies have shown that concentrations from 5-100ng/mL do induce goblet cell hyperplasia, including in human bronchial epithelial cells (Yoshisue and Hasegawa, 2004).

It has been shown that two weeks but not one week of human nasal epithelial cell differentiation and IL13 treatment showed a decrease in proportion of ciliated cells (shown by glutamylated tubulin protein expression) (Laouikili et al., 2001), however other studies showed that IL13-induced ciliated to goblet cell differentiation were observed in as little as 3-5 days cultured human airway epithelium, mouse tracheal epithelial cells and a Sendai virus mouse model (Gomperts et al., 2007), (Fujisawa et al., 2008), (Tyner et al., 2006). This difference may be due to the difference in cell types used in these experiments. Ciliated cells of pseudostratified airway epithelium do not become mucous cells after ovalbumin (OVA) challenge for 48 hours which may be due to insufficient time for OVA-induced IL13 upregulation and subsequent effects (Pardo-Saganta et al., 2013). This AOP is focused on mucus hypersecretion in the context of COPD and not asthma, which could act differently.

IL13 can also act independently of EGFR, stimulating IL13RA2 and IL4RA receptors which lead to downstream STAT signaling. Description of this pathway is appropriate for a separate AOP.

EGFR involvement has been shown in Clara cell transdifferentiation in a Sendai virus mouse model (Tyner et al., 2006), while another study suggested that IL13 and IL4 receptor IL4RA was important for Clara cell mucus production in ovalbumin-induced mouse lung (Kuperman et al., 2005). Since many of these studies used Clara cell marker CCSP which has been found to drive recombination in ciliated airway epithelial cells, it is unclear whether it is Clara cells or ciliated cells which are transdifferentiating.

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?

It has been proposed that the effects of IL13 and IL4 on differentiation to goblet cells is concentration-dependent in human bronchial epithelial cells, with 1ng/ml inducing an increase in goblet cell density acting through MAPK and p38 MAPK but not EGFR and 10ng/ml inducing a reduction in goblet cell density (Atherton et al., 2003). Other studies have agreed with this finding, with 1ng/mL IL13 leading to an increase in goblet hyperplasia in human bronchial epitehlial cells (Turner et al., 2011) and 5ng/mL having a lack of effect inducing goblet cell differentiation in nasal epithelial cells (Kim et al., 2002). On the contrary, multiple studies have shown that concentrations from 5-100ng/mL do induce goblet cell hyperplasia in human bronchial epithelial cells, human nasal epithelial cells, cultured human differentiated airway epithelial tissue, cultured guinea pig tracheal epithelium, and mouse tracheal epithelial cells (Yoshisue and Hasegawa, 2004), (Laoukili et al., 2001), (Gomperts et al., 2007), (Kondo et al., 2002), (Fujisawa et al., 2008).

It has also been proposed that two weeks of differentiation is necessary to see the effects (Laoukili et al., 2001) and could explain why differentiation was not observed in a two day OVA-induced murine model (Pardo-Saganta et al., 2013) or seven day human nasal epithelial cell model (Kim et al., 2002). On the contrary, IL13-induced goblet cell metaplasia was also observed in short term experiments of 3-5 days in cultured human airway epithelium, mouse tracheal epithelial cells and a Sendai virus mouse model (Gomperts et al., 2007), (Fujisawa et al., 2008), (Tyner et al., 2006).

Evidence Supporting Taxonomic Applicability

There are many human studies demonstrating transdifferentiation from ciliated to goblet cells including in 3D human airway epithelial models (Gomperts et al., 2007), human bronchial or nasal epithelial cells in vitro (Yoshisue and Hasegawa, 2004, Turner et al., 2011, Laoukili et al., 2001) and in COPD patients (Tyner et al., 2006).

Two mouse studies have demonstrated ciliated cell transdifferentiation and goblet metaplasia in response to virus and/or IL13 (Tyner et al., 2006), (Fujisawa et al., 2008).

Two rat studies have demonstrated IL-13 and/or EGFR involvement in goblet cell metaplasia/hyperplasia, however no rat studies have directly measured transdifferentiation of ciliated to goblet cells to our knowledge (Shim et al., 2001), (Takeyama et al., 2008).

A guinea pig study showed that IL13 but not Il4 induced goblet cell metaplasia in primary epithelial cells from guinea pig trachea 14 days at 10ng/mL shown by a large number of fully differentiated goblet cells and smaller numbers of ciliated cells, increased PAS staining and increased MUC5AC staining (Kondo et al., 2002).

References


1. Atherton, H.C., Jones, G., and Danahay, H. (2003). IL-13-induced changes in the goblet cell density of human bronchial epithelial cell cultures: MAP kinase and phosphatidylinositol 3-kinase regulation. Am. J. Physiol. Lung Cell. Mol. Physiol. 285, L730–L739.

2. Breuer, R., Zajicek, G., Christensen, T.G., Lucey, E.C., and Snider, G.L. (1990). Cell Kinetics of Normal Adult Hamster Bronchial Epithelium in the Steady State. Am. J. Respir. Cell Mol. Biol. 2, 51–58.

3. 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.

4. Donnelly, G.M., Haack, D.G., and Heird, C.S. (1982). Tracheal epithelium: cell kinetics and differentiation in normal rat tissue. Cell Tissue Kinet. 15, 119–130.

5. Fujisawa, T., Ide, K., Holtzman, M.J., Suda, T., Suzuki, K., Kuroishi, S., Chida, K., and Nakamura, H. (2008). Involvement of the p38 MAPK pathway in IL-13-induced mucous cell metaplasia in mouse tracheal epithelial cells. Respirol. Carlton Vic 13, 191–202.

6. Gomperts, B.N., Kim, L.J., Flaherty, S.A., and Hackett, B.P. (2007). IL-13 regulates cilia loss and foxj1 expression in human airway epithelium. Am. J. Respir. Cell Mol. Biol. 37, 339–346.

7. Kim, S., Shim, J., Burgerl, P., Ueki, I., Dao-Pick, T., Tam, D., and Nadel, J. (2002). IL-13-induced Clara cell secretory protein expression in airway epithelium: role of EGFR signaling pathway. Am J Physiol Lung Cell Mol Physiol 283, L67–L75.

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9. Laoukili, J., Perret, E., Willems, T., Minty, A., Parthoens, E., Houcine, O., Coste, A., Jorissen, M., Marano, F., Caput, D., et al. (2001). IL-13 alters mucociliary differentiation and ciliary beating of human respiratory epithelial cells. J. Clin. Invest. 108, 1817–1824.

10. Lawson, G.W., Van Winkle, L.S., Toskala, E., Senior, R.M., Parks, W.C., and Plopper, C.G. (2002). Mouse strain modulates the role of the ciliated cell in acute tracheobronchial airway injury-distal airways. Am. J. Pathol. 160, 315–327.

11. Pardo-Saganta, A., Law, B.M., Gonzalez-Celeiro, M., Vinarsky, V., and Rajagopal, J. (2013). Ciliated cells of pseudostratified airway epithelium do not become mucous cells after ovalbumin challenge. Am. J. Respir. Cell Mol. Biol. 48, 364–373.

12. Park, K.-S., Wells, J.M., Zorn, A.M., Wert, S.E., Laubach, V.E., Fernandez, L.G., and Whitsett, J.A. (2006). Transdifferentiation of ciliated cells during repair of the respiratory epithelium. Am. J. Respir. Cell Mol. Biol. 34, 151–157.

13. Rawlins, E.L., and Hogan, B.L.M. (2008). Ciliated epithelial cell lifespan in the mouse trachea and lung. Am. J. Physiol. - Lung Cell. Mol. Physiol. 295, L231–L234.

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15. Shim, J.J., Dabbagh, K., Ueki, I.F., Dao-Pick, T., Burgel, P.R., Takeyama, K., Tam, D.C., and Nadel, J.A. (2001). IL-13 induces mucin production by stimulating epidermal growth factor receptors and by activating neutrophils. Am. J. Physiol. Lung Cell. Mol. Physiol. 280, L134–L140.

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17. Sisson, J.H., Papi, A., Beckmann, J.D., Leise, K.L., Wisecarver, J., Brodersen, B.W., Kelling, C.L., Spurzem, J.R., and Rennard, S.I. (1994). Smoke and viral infection cause cilia loss detectable by bronchoalveolar lavage cytology and dynein ELISA. Am. J. Respir. Crit. Care Med. 149, 205–213.

18. Staudt, M., Rogalski, A., Tilley, A., Kaner, R., Harvey, B., and Crystal, R. (2014). Smoking Is Associated With A Loss Of Ciliated Cells Throughout The Airways. Am J Respir Crit Care Med 189 A4097.

19. 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.

20. 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. Respir. Cell Mol. Biol. 44, 276–284.

21. 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.

22. Yoshisue, H., and Hasegawa, K. (2004). Effect of MMP/ADAM inhibitors on goblet cell hyperplasia in cultured human bronchial epithelial cells. Biosci Biotechnol Biochem 68, 2024–2031.