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Key Event Title
Increase, goblet cell number
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Decreased lung function||KeyEvent||Karsta Luettich (send email)||Under development: Not open for comment. Do not cite||Under Development|
Key Event Description
Goblet cell is a mucus secreting cell type that can be found in epithelial mucosa of the intestine, lung, and eye. Goblet cells are necessary for mucosal epithelial homeostasis as well as for the appropriate function of both innate and adaptive immunity. Alterations in goblet cell numbers are characteristics of some pathologies. In the airway, the increased number of goblet cells is generally associated with diseases, such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD). While some disorders of the intestine and conjunctiva are associated with the decrease in goblet cell numbers, Crohn’s disease, cystic fibrosis, allergic conjunctivitis, and inverted mucoepidermoid papilloma have increased number of goblet cells (McCauley & Guasch, 2015). Goblet cell hyperplasia (GCH) can arise following airway injury and is defined by otherwise intact epithelium with an increase in the number of goblet cells (Hao et al, 2012; SAETTA et al, 2000). Pathologists define goblet cell metaplasia as apparent loss of ciliated or club cells with an increase of goblet cells, without an apparent increase in the total number of epithelial cells (Lumsden et al, 1984; Reader et al, 2003; Shimizu et al, 1996). The increased number of goblet cells via proliferation has been demonstrated in the rat intestine (Hino et al, 2012) and eye (Gu et al, 2008; Li et al, 2013; Shatos et al, 2008) in response dietary fiber and EGFR stimulation, respectively.
Evidence for Perturbation by Stressor
Several studies have shown that the number of goblet cells increase in response to various stressors. Cigarette smoke exposure resulted in the increase in the number of goblet cells in the airway of rats (Kato et al, 2020; Xiao et al, 2011), mice (Mebratu et al, 2011; Yang et al, 2020), dogs (Park et al, 1977), monkeys (Manevski et al, 2022), and in human airway epithelial cells cultured in air-liquid interface (Haswell et al, 2010; Haswell et al, 2021). Similarly, exposure of mice or rats to nebulized acrolein resulted in goblet cell metaplasia in the airways (Chen et al, 2010; Liu et al, 2009; Wang et al, 2009) and the treatment of primary human bronchial epithelial cells differentiated at the air-liquid interface with up to 1 µM acrolein induced a concentration dependent increase in the percentage of MUC5A-positive cells (Haswell et al., 2010). Ozone has also been shown to contribute to the increased number of goblet cells in the airways of mice (Jang et al, 2006; Larsen et al, 2010) and rats (Wagner et al, 2003). The goblet cell numbers also increased in the intestine of rats infected with Hymenolepis diminuta (tapeworm) (Webb et al, 2007) and mice infected with Nippostrongylus brasiliensis (hookworm) (Turner et al, 2013). Finally, air pollution was shown to trigger GCH in the eye (Novaes et al, 2007).
How It Is Measured or Detected
There are few standard ways to measure the increased number of goblet cells in a tissue specimen or cultured cells:
The mucin-producing secretory granules of goblet cells can be identified easily by light or electron microscopy (Rogers, 1994). The stages of metaplastic transformation can be identified as early cilia-goblet cells, late cilia-goblet, and mature goblet cells using transmission electron micrographs (Tyner et al, 2006). In laboratory animals, GCH may be identified by a pathologist as an increase in the number of goblet cells in an epithelium which normally contains only few goblet cells (Harkema & Hotchkiss, 1993).
The increased number of goblet cells can be measured by staining the tissue or ALI culture with antibody recognizing MUC5 and counting the number of labeled cells/mm of epithelium or percentage of positive cells in the epithelium (Casalino-Matsuda et al, 2006; Jia et al, 2021; Lou et al, 1998; Tyner et al., 2006).
Alternatively, many researchers use hematoxylin and eosin to stain the entire epithelial area (total number of nuclei) and Alcian blue (AB)-periodic acid-Schiff (PAS) to stain the intracellular mucous glycoconjugates, marking goblet cells. The change in goblet cell numbers is defined by the change in the proportion of AB-PAS-stained surface of the entire epithelial cell area over a length of 2 mm of the basal lamina (Takeyama et al, 2008).
AB staining can be combined with goblet cell marker, Clca3, expressed as the goblet cell area / bronchial basement membrane (Leverkoehne et al, 2006; Song et al, 2016).
Bromo-deoxyuridine (BrDU) incorporation can be used to identify the proliferating goblet cells in tissue specimens (GRANT & Specian, 1998; Hino et al., 2012).
Proliferating Cell Nuclear Antigen 19A2 (PCNA) staining was used to identify proliferating goblet cells in the crypt of the intestinal wall in rabbits (GRANT & Specian, 1998).
In a culture that consist solely of goblet cells (e.g., from conjunctiva), increase in goblet cells via proliferation was measured by Ki-67 immunofluorescent staining (Gu et al., 2008).
Domain of Applicability
The increased number of goblet cells in response to stressors can be found in rats, mice, rabbits, guinea pigs, and humans.
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