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Event: 2117

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Increase, goblet cell number

Short name
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Increase, goblet cell number
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Biological Context

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Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
goblet cell increased

Key Event Overview

AOPs Including This Key Event

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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

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
rat Rattus norvegicus NCBI
mouse Mus musculus NCBI
rabbit Oryctolagus cuniculus NCBI
guinea pig Cavia porcellus NCBI
human Homo sapiens NCBI

Life Stages

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Sex Applicability

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Term Evidence
Unspecific

Key Event Description

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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

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

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

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

The increased number of goblet cells in response to stressors can be found in rats, mice, rabbits, guinea pigs, and humans.  

References

List of the literature that was cited for this KE description. More help

Casalino-Matsuda SM, Monzón ME, Forteza RM (2006) Epidermal growth factor receptor activation by epidermal growth factor mediates oxidant-induced goblet cell metaplasia in human airway epithelium. American journal of respiratory cell and molecular biology 34: 581-591 

Chen Y-J, Chen P, Wang H-X, Wang T, Chen L, Wang X, Sun B-B, Liu D-S, Xu D, An J (2010) Simvastatin attenuates acrolein-induced mucin production in rats: involvement of the Ras/extracellular signal-regulated kinase pathway. International immunopharmacology 10: 685-693 

GRANT TD, Specian RD (1998) Proliferation of goblet cells and vacuolated cells in the rabbit distal colon. The Anatomical Record: An Official Publication of the American Association of Anatomists 252: 41-48 

Gu J, Chen L, Shatos MA, Rios JD, Gulati A, Hodges RR, Dartt DA (2008) Presence of EGF growth factor ligands and their effects on cultured rat conjunctival goblet cell proliferation. Experimental Eye Research 86: 322-334 

Hao Y, Kuang Z, Walling BE, Bhatia S, Sivaguru M, Chen Y, Gaskins HR, Lau GW (2012) Pseudomonas aeruginosa pyocyanin causes airway GCH and metaplasia and mucus hypersecretion by inactivating the transcriptional factor FoxA2. Cellular microbiology 14: 401-415 

Harkema JR, Hotchkiss JA (1993) Ozone- and endotoxin-induced mucous cell metaplasias in rat airway epithelium: Novel animal models to study toxicant-induced epithelial transformation in airways. Toxicology Letters 68: 251-263 

Haswell LE, Hewitt K, Thorne D, Richter A, Gaça MD (2010) Cigarette smoke total particulate matter increases mucous secreting cell numbers in vitro: a potential model of goblet cell hyperplasia. Toxicology in Vitro 24: 981-987 

Haswell LE, Smart D, Jaunky T, Baxter A, Santopietro S, Meredith S, Camacho OM, Breheny D, Thorne D, Gaca MD (2021) The development of an in vitro 3D model of goblet cell hyperplasia using MUC5AC expression and repeated whole aerosol exposures. Toxicology Letters 347: 45-57 

Hino S, Takemura N, Sonoyama K, Morita A, Kawagishi H, Aoe S, Morita T (2012) Small intestinal goblet cell proliferation induced by ingestion of soluble and insoluble dietary fiber is characterized by an increase in sialylated mucins in rats. The Journal of nutrition 142: 1429-1436 

Jang A-S, Choi I-S, Lee J-H, Park C-S, Park C-S (2006) Prolonged ozone exposure in an allergic airway disease model: adaptation of airway responsiveness and airway remodeling. Respiratory Research 7: 1-8 

Jia Z, Bao K, Wei P, Yu X, Zhang Y, Wang X, Wang X, Yao L, Li L, Wu P (2021) EGFR activation-induced decreases in claudin1 promote MUC5AC expression and exacerbate asthma in mice. Mucosal Immunology 14: 125-134 

Kato K, Chang EH, Chen Y, Lu W, Kim MM, Niihori M, Hecker L, Kim KC (2020) MUC1 contributes to goblet cell metaplasia and MUC5AC expression in response to cigarette smoke in vivo. American Journal of Physiology-Lung Cellular and Molecular Physiology 319: L82-L90 

Larsen SrT, Matsubara S, McConville G, Poulsen SS, Gelfand EW (2010) Ozone increases airway hyperreactivity and mucus hyperproduction in mice previously exposed to allergen. Journal of Toxicology and Environmental Health, Part A 73: 738-747 

Leverkoehne I, Holle H, Anton F, Gruber AD (2006) Differential expression of calcium-activated chloride channels (CLCA) gene family members in the small intestine of cystic fibrosis mouse models. Histochemistry and cell biology 126: 239-250 

Li D, Shatos MA, Hodges RR, Dartt DA (2013) Role of PKCα activation of Src, PI-3K/AKT, and ERK in EGF-stimulated proliferation of rat and human conjunctival goblet cells. Investigative ophthalmology & visual science 54: 5661-5674 

Liu D-S, Wang T, Han S-X, Dong J-J, Liao Z-L, He G-M, Chen L, Chen Y-J, Xu D, Hou Y (2009) p38 MAPK and MMP-9 cooperatively regulate mucus overproduction in mice exposed to acrolein fog. International immunopharmacology 9: 1228-1235 

Lou Y-P, Takeyama K, Grattan KM, Lausier JA, Ueki IF, Agusti C, Nadel JA (1998) Platelet-activating factor induces goblet cell hyperplasia and mucin gene expression in airways. American journal of respiratory and critical care medicine 157: 1927-1934 

Lumsden AB, McLean A, Lamb D (1984) Goblet and Clara cells of human distal airways: evidence for smoking induced changes in their numbers. Thorax 39: 844-849 

Manevski M, Devadoss D, Long C, Singh SP, Nasser MW, Borchert GM, Nair MN, Rahman I, Sopori M, Chand HS (2022) Increased Expression of LASI lncRNA Regulates the Cigarette Smoke and COPD Associated Airway Inflammation and Mucous Cell Hyperplasia. Frontiers in Immunology 13 

McCauley HA, Guasch G (2015) Three cheers for the goblet cell: maintaining homeostasis in mucosal epithelia. Trends in molecular medicine 21: 492-503 

Mebratu YA, Schwalm K, Smith KR, Schuyler M, Tesfaigzi Y (2011) Cigarette smoke suppresses Bik to cause epithelial cell hyperplasia and mucous cell metaplasia. American journal of respiratory and critical care medicine 183: 1531-1538 

Novaes P, do Nascimento Saldiva PH, Kara-José N, Macchione M, Matsuda M, Racca L, Berra A (2007) Ambient levels of air pollution induce goblet-cell hyperplasia in human conjunctival epithelium. Environmental health perspectives 115: 1753-1756 

Park SS, Kikkawa Y, Goldring IP, Daly MM, Zelefsky M, Shim C, Spierer M, Morita T (1977) An animal model of cigarette smoking in beagle dogs: correlative evaluation of effects on pulmonary function, defense, and morphology. American Review of Respiratory Disease 115: 971-979 

Reader JR, Tepper JS, Schelegle ES, Aldrich MC, Putney LF, Pfeiffer JW, Hyde DM (2003) Pathogenesis of mucous cell metaplasia in a murine asthma model. American Journal of Pathology 162: 2069-2078 

Rogers D (1994) Airway goblet cells: responsive and adaptable front-line defenders. European Respiratory Journal 7: 1690-1706 

SAETTA M, TURATO G, BARALDO S, ZANIN A, BRACCIONI F, MAPP CE, MAESTRELLI P, CAVALLESCO G, PAPI A, FABBRI LM (2000) Goblet cell hyperplasia and epithelial inflammation in peripheral airways of smokers with both symptoms of chronic bronchitis and chronic airflow limitation. American journal of respiratory and critical care medicine 161: 1016-1021 

Shatos MA, Gu J, Hodges RR, Lashkari K, Dartt DA (2008) ERK/p44p42 mitogen-activated protein kinase mediates EGF-stimulated proliferation of conjunctival goblet cells in culture. Investigative Ophthalmology & Visual Science 49: 3351-3359 

Shimizu T, Takahashi Y, Kawaguchi S, Sakakura Y (1996) Hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium induced by endotoxin. American journal of respiratory and critical care medicine 153: 1412-1418 

Song L, Tang H, Liu D, Song J, Wu Y, Qu S, Li Y (2016) The chronic and short-term effects of gefinitib on airway remodeling and inflammation in a mouse model of asthma. Cellular Physiology and Biochemistry 38: 194-206 

Takeyama K, Tamaoki J, Kondo M, Isono K, Nagai A (2008) Role of epidermal growth factor receptor in maintaining airway goblet cell hyperplasia in rats sensitized to allergen. Clinical & Experimental Allergy 38: 857-865 

Turner J-E, Stockinger B, Helmby H (2013) IL-22 mediates goblet cell hyperplasia and worm expulsion in intestinal helminth infection. PLoS pathogens 9: e1003698 

Tyner JW, Kim EY, Ide K, Pelletier MR, Roswit WT, Morton JD, Battaile JT, Patel AC, Patterson GA, Castro M et al (2006) Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-13 transdifferentiation signals. Journal of Clinical Investigation 116: 309-321 

Wagner JG, Van Dyken SJ, Wierenga JR, Hotchkiss JA, Harkema JR (2003) Ozone exposure enhances endotoxin-induced mucous cell metaplasia in rat pulmonary airways. Toxicological Sciences 74: 437-446 

Wang T, Liu Y, Chen L, Wang X, Hu X-R, Feng Y-L, Liu D-S, Xu D, Duan Y-P, Lin J (2009) Effect of sildenafil on acrolein-induced airway inflammation and mucus production in rats. European Respiratory Journal 33: 1122-1132 

Webb R, Hoque T, Dimas S (2007) Expulsion of the gastrointestinal cestode, Hymenolepis diminuta by tolerant rats: evidence for mediation by a Th2 type immune enhanced goblet cell hyperplasia, increased mucin production and secretion. Parasite immunology 29: 11-21 

Xiao J, Wang K, Feng Y-l, Chen X-r, Xu D, Zhang M-k (2011) Role of extracellular signal-regulated kinase 1/2 in cigarette smoke-induced mucus hypersecretion in a rat model. Chinese medical journal 124: 3327-3333 

Yang T, Wang H, Li Y, Zeng Z, Shen Y, Wan C, Wu Y, Dong J, Chen L, Wen F (2020) Serotonin receptors 5-HTR2A and 5-HTR2B are involved in cigarette smoke-induced airway inflammation, mucus hypersecretion and airway remodeling in mice. International immunopharmacology 81: 106036