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 Mucus Hypersecretion Directly Leads to Moderate Moderate

Taxonomic Applicability

Name Scientific Name Evidence Links

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

Ciliated cell transdifferentiation to goblet cells is biologically plausible as a number of studies have shown this to occur in response to IL13 by a mix of features characteristic of each cell type within a cell (Tyner et al., 2006), (Laoukili et al., 2001), (Gomperts et al., 2007) or fluorescent labeling from ciliated cells detected in goblet cells after differentiation (Turner et al., 2011). One study has shown EGFR involvement via IL13-induced TGFA (Yoshisue and Hasegawa, 2004) and another study showed ROS-induced EGF and subsequent EGFR activation leading to an increase in goblet cells and decrease in ciliated cells (Casalino-Matsuda et al., 2006).

Ciliated cell transdifferentiation conflicts with the traditional dogma that ciliiated cells are terminally differentiated under normal conditions (Rawlins and Hogan, 2008), and 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) and there is a wide variety of responses in epithelial repair among different mouse strains (Lawson et al., 2002).

Empirical Support for Linkage

Include consideration of temporal concordance here

Uncertainties or Inconsistencies

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?

Evidence Supporting Taxonomic Applicability

References