The Adverse Outcome Pathway for Oxidative Stress-Mediated EGFR Activation Leading to Decreased Lung Function

Abstract

The Adverse Outcome Pathway (AOP) framework provides a means to outline a knowledge-driven sequence of events from exposure to adverse outcome. As a concept, AOPs have been readily accepted by the toxicology community as a means to organize available mechanistic information linking exposures to toxic effects in a standardized way encompassing all organizational levels of a given biological system. However, there is also an inherent benefit in applying AOPs to health outcomes that are not necessarily linked to standard toxicological end points, for example, in the context of predicting disease risk or in drug development. In this study, we propose an AOP for decreased lung function that originates in oxidative stress-mediated epidermal growth factor receptor activation in the airway epithelium. This article provides an overview of the supporting evidence for key events (KEs) on the molecular, cellular, tissue/organ, and organism level and how they relate to each other through key event relationships (KERs). The essentiality of the identified KEs, as well as the biological plausibility of the KERs, is also assessed. Moreover, the envisioned application of the proposed AOP is discussed, highlighting the utility of the AOP framework for developing preclinical tests that could prove useful in public health risk assessment for long-term e-cigarette use.

Construction of a Suite of Computable Biological Network Models Focused on Mucociliary Clearance in the Respiratory Tract

“…Oxidative stress is a well-described trigger of the epidermal growth factor receptor (EGFR) signaling pathway that leads to mucus hypersecretion (Takeyama et al, 1999, 2001; Perrais et al, 2002; Hewson et al, 2004; Casalino-Matsuda et al, 2006; Hao et al, 2014). We recently published an adverse outcome pathway that describes the events that follow oxidative stress-mediated EGFR activation to goblet cell hyperplasia/metaplasia and decreased lung function following mucus overproduction (Luettich et al, 2017).…”

Influenza A virus diffusion through mucus gel networks

“…The inflammatory response to IAV infection is known to increase reactive oxygen species (ROS) production and cytokine expression resulting in acute lung injury (45). In response to ROS and oxidative stress, the epidermal growth factor (EGFR) pathway, responsible for mucin hypersecretion, becomes activated leading to increased mucus concentration in the airway lumen (46,47). In addition, prior studies have found ROS and oxidative stress can increase the elasticity of airway mucus (43), attributed to the oxidation of mucin cysteine domains leading to formation of mucin-mucin disulfide crosslinks (48).…”

Developing Network-Based Systems Toxicology by Combining Transcriptomics Data with Literature Mining and Multiscale Quantitative Modeling

“…We have contributed to the development of two AOPs for the common disorders resulting from long-term smoking and published them in the AOP wiki [75]. The first AOP maps the events from epidermal growth factor receptor activation by oxidative stress to decreased lung function [76], and the second AOP illustrates the different steps that are required for oxidative stress to lead to disruption in endothelial nitric oxide bioavailability and, finally, to hypertension [77]. These AOPs were built following the requirements by the Organization for Economic Co-operation and Development (OECD) [78].…”