Key Event Title
Key Event Component
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|EGFR Activation Leading to Decreased Lung Function||KeyEvent|
Level of Biological Organization
|ferret||Mustela putorius furo||Not Specified||NCBI|
|guinea pig||Cavia porcellus||Strong||NCBI|
Life Stage Applicability
|3 to < 6 years||Moderate|
|6 to < 11 years||Moderate|
|11 to < 16 years||Moderate|
How This Key Event Works
Goblet cell hyperplasia refers to the increase in goblet cell numbers and is as common feature of airway epithelia in asthma and other respiratory diseases. It can arise from sustained proliferation of this cell population following airway injury by, for example, exposure to allergens, pathogens, cigarette smoke and other inhalation exposures (Miyabara et al., 1998; Nagao et al., 2003; Saetta et al., 2000; van Hove et al., 2009; Walter et al., 2002; Hao et al., 2014; Lukacs et al., 2010; Hao et al., 2013; Yageta et al., 2014; Nie et al., 2012; Hegab et al., 2007; Kim et al., 2016).
Following EGFR activation, classical downstream activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, also known as Raf/Ras/MAPK/ERK pathway, increases airway epithelial cell proliferation (Lemjabbar et al., 2003; Kim et al., 2005; Hackel et al., 1999) and facilitates epithelial wound repair (Burgel & Nadel, 2004; Van Winkle et al., 1997; Allahverdian et al., 2010). While there is evidence that increased goblet cell proliferation may be the underlying cause of goblet cell hyperplasia (GCH; Silva et al., 2012), the key players mediating an increase in airway goblet cell numbers following EGFR activation are still largely unexplored. Basal epithelial cells which exhibit stem cell-like properties have been postulated to function as a source of goblet cells in injured airways, utilizing cell fate pathways that favor secretory cells over other cell populations (Rock et al., 2009). However, both in vitro studies and studies in mouse models of asthma, COPD, and viral infection indicate that transdifferentiation of ciliated or club cells into goblet cells, which is referred to as goblet cell metaplasia (GCM), more likely contributes to the expansion of this cell population in the airways (Tyner et al., 2006; Lumsden et al., 1984; Reader et al., 2003; Turner et al., 2011; Evans et al., 2004; Lamb et al., 1968; Shimizu et al., 1998). Furthermore, such increases in the number of goblet cells are suppressed when EGFR activity is inhibited (Tyner et al., 2006).
How It Is Measured or Detected
Goblet cells are mucin-producing columnar epithelial cells, and their secretory granules can be identified easily by light or electron microscopy (Rogers, 1994). However, MUC5AC immunohistochemical staining is typically used to identify and enumerate this cell type in tissue sections, even though this is semi-quantitative at best. Alternatively, staining of tissue sections with Alcian blue (AB) or AB in combination with periodic acid–Schiff (PAS) can also be used to highlight and count mucus-containing goblet cells. In addition, the simultaneous detection and quantification of proliferation markers such as PCNA or Ki-67 may prove helpful in identifying proliferating goblet cells following airway injury.
In laboratory animals, GCH may be idenitfied by a pathologist as an increase in the number of goblet cells in an epithelium which normally contains some goblet cells (Harkema and Hotchkiss, 1993). Similarly, a trained pathologist may assign a score for the extent of GCH occurring in human airway epithelial tissues, and although no standard for this assessment exists, this appears to be a clinically accepted approach.
Evidence Supporting Taxonomic Applicability
Goblet cell hyperplasia was reported in respiratory epithelia of humans, mice and rats following various inhalation exposures (Saetta et al., 2000; Takeyama et al., 2008; Tesfaigzi et al., 2000; Werley et al., 2016). Although GCH is a common feature of adaptation to respiratory irritants and/or airway epithelial repair among these species, some species differences exist with respect to the sensitivity toward certain exposures (Wolf et al., 1995; NTP, 1994).
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Burgel, P., and Nadel, J. (2004). Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium. Thorax 59, 992-996.
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