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Key Event Title
Occurrence, Hyperplasia of goblet cells
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
Key Event Description
Goblet cell hyperplasia refers to an increase in goblet cell numbers and is a 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).
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 identified by a pathologist as an increase in the number of goblet cells in an epithelium which normally contains only few goblet cells (Harkema and Hotchkiss, 1993). An experienced 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.
Domain of Applicability
Goblet cell hyperplasia (GCH) was reported in respiratory epithelia of humans, mice, rats, ferrets and dogs following various inhalation exposures (Park et al.,1977; 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).
Allahverdian, S., Wang, A., Singhera, G.K., Wong, B.W., and Dorscheid, D.R. (2010). Sialyl Lewis X modification of the epidermal growth factor receptor regulates receptor function during airway epithelial wound repair. Clin Exp Allergy 40, 607-618.
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.
Evans, C.M., Williams, O.W., Tuvim, M.J., Nigam, R., Mixides, G.P., Blackburn, M.R., DeMayo, F.J., Burns, A.R., Smith, C., Reynolds, S.D., et al. (2004). Mucin Is produced by Clara cells in the proximal airways of antigen-challenged mice. Am J Resp Cell Mol Biol 31, 382-394.
Hackel, P.O., Zwick, E., Prenzel, N., and Ullrich, A. (1999). Epidermal growth factor receptors: critical mediators of multiple receptor pathways. Curr Opin Cell Biol 11, 184-189.
Hao, Y., Kuang, Z., Jing, J., Miao, J., Mei, L.Y., Lee, R.J., Kim, S., Choe, S., Krause, D.C., and Lau, G.W. (2014). Mycoplasma pneumoniae modulates STAT3-STAT6/EGFR-FOXA2 signaling to induce overexpression of airway mucins. Infect Immun 82, 5246-5255.
Hao, Y., Kuang, Z., Xu, Y., Walling, B.E., and Lau, G.W. (2013). Pyocyanin-induced mucin production is associated with redox modification of FOXA2. Respir Res 14, 82-82.
Harkema, J.R., and Hotchkiss, J.A. (1993). Ozone- and endotoxin-induced mucous cell metaplasias in rat airway epithelium: Novel animal models to study toxicant-induced epithelial transformation in airways. Toxicol Lett 68, 251-263.
Haswell, L.E., Hewitt, K., Thorne, D., Richter, A., and Gaça, M.D. (2010). Cigarette smoke total particulate matter increases mucous secreting cell numbers in vitro: A potential model of goblet cell hyperplasia. Toxicol. in Vitro 24, 981-987.
Haswell, L.E., Smart, D., Jaunky, T., Baxter, A., Santopietro, S., Meredith, S., et al. (2021). The development of an in vitro 3D model of goblet cell hyperplasia using MUC5AC expression and repeated whole aerosol exposures. Toxicol. Lett. 347, 45-57.
Hegab, A.E., Sakamoto, T., Nomura, A., Ishii, Y., Morishima, Y., Iizuka, T., Kiwamoto, T., Matsuno, Y., Homma, S., and Sekizawa, K. (2007). Niflumic acid and AG-1478 reduce cigarette smoke-induced mucin synthesis: The role of hCLCA1. Chest 131, 1149-1156.
Jang, A.-S., Choi, I.-S., Lee, J.-H., Park, C.-S., and Park, C.-S. (2006). Prolonged ozone exposure in an allergic airway disease model: adaptation of airway responsiveness and airway remodeling. Respir. Res. 7, 1-8.
Kim, S., Schein, A.J., and Nadel, J.A. (2005). E-cadherin promotes EGFR-mediated cell differentiation and MUC5AC mucin expression in cultured human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 289, L1049-L1060.
Kim, B.-G., Lee, P.-H., Lee, S.-H., Kim, Y.-E., Shin, M.-Y., Kang, Y., Bae, S.-H., Kim, M.-J., Rhim, T., Park, C.-S., et al. (2016). Long-Term Effects of Diesel Exhaust Particles on Airway Inflammation and Remodeling in a Mouse Model. Allergy Asthma Immunol Res 8, 246-256.
Lamb, D., and Reid, L. (1968). Mitotic rates, goblet cell increase and histochemical changes in mucus in rat bronchial epithelium during exposure to sulphur dioxide. J Pathol Bacteriol 96, 97-111.
Lemjabbar, H., Li, D., Gallup, M., Sidhu, S., Drori, E., and Basbaum, C. (2003). Tobacco smoke-induced lung cell proliferation mediated by tumor necrosis factor alpha-converting enzyme and amphiregulin. J Biol Chem 278, 26202-26207.
Lukacs, N.W., Smit, J.J., Nunez, G., and Lindell, D.M. (2010). Respiratory Virus-induced TLR7 activation controls IL-17 associated Increase in mucus via IL-23 regulation: Respiratory virus induced immune environment relies on TLR7-mediated pathways to preserve a non-pathogenic response and regulates IL-17 production. J Immunol 185, 2231-2239.
Lumsden, A.B., McLean, A., and Lamb, D. (1984). Goblet and Clara cells of human distal airways: evidence for smoking induced changes in their numbers. Thorax 39, 844-849.
Miyabara, Y., Ichinose, T., Takano, H., Lim, H.-B., and Sagai, M. (1998). Effects of diesel exhaust on allergic airway inflammation in mice. J Allergy Clin Immunol 102, 805-812.
Nagao, K., Tanaka, H., Komai, M., Masuda, T., Narumiya, S., and Nagai, H. (2003). Role of Prostaglandin I2 in Airway Remodeling Induced by Repeated Allergen Challenge in Mice. Am J Resp Cell Mol Biol 29, 314-320.
Nie, Y.-C., Wu, H., Li, P.-B., Luo, Y.-L., Zhang, C.-C., Shen, J.-G., and Su, W.-W. (2012). Characteristic comparison of three rat models induced by cigarette smoke or combined with LPS: to establish a suitable model for study of airway mucus hypersecretion in chronic obstructive pulmonary disease. Pulm Pharmacol Ther 25, 349-356.
NTP (1994). NTP Toxicology and Carcinogenesis Studies of Ozone (CAS No. 10028-15-6) and Ozone/NNK (CAS No. 10028-15-6/64091-91-4) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). National Toxicology Program technical report series 440, 1.
Park, S.S., Kikkawa, Y., Goldring, I.P., Daly, M.M., Zelefsky, M., Shim, C., et al. (1977). An animal model of cigarette smoking in beagle dogs: correlative evaluation of effects on pulmonary function, defense, and morphology. Am. Rev. Respir. Dis. 115, 971-979.
Reader, J.R., Tepper, J.S., Schelegle, E.S., Aldrich, M.C., Putney, L.F., Pfeiffer, J.W., and Hyde, D.M. (2003). Pathogenesis of mucous cell metaplasia in a murine asthma model. Am J Pathol 162, 2069-2078.
Rock, J.R., Onaitis, M.W., Rawlins, E.L., Lu, Y., Clark, C.P., Xue, Y., Randell, S.H., and Hogan, B.L. (2009). Basal cells as stem cells of the mouse trachea and human airway epithelium. PNAS 106, 12771-12775.
Rogers, D. (1994). Airway goblet cells: responsive and adaptable front-line defenders. Eur Respir J 7, 1690-1706.
Saetta, M., Turato, G., Baraldo, S., Zanin, A., Braccioni, F., Mapp, C.E., Maestrelli, P., Cavallesco, G., Papi, A., and Fabri, L.M. (2000). Goblet Cell Hyperplasia and Epithelial Inflammation in Peripheral Airways of Smokers with Both Symptoms of Chronic Bronchitis and Chronic Airflow Limitation. Am J Resp Crit Care Med 161, 1016-1021.
Shimizu, T., Takahashi, Y., Kawaguchi, S., and Sakakura, Y. (1996). Hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium induced by endotoxin. Am J Resp Crit Care Med 153, 1412-1418.
Silva, M.A., and Bercik, P. (2012). Macrophages are related to goblet cell hyperplasia and induce MUC5B but not MUC5AC in human bronchus epithelial cells. Lab Invest 92, 937-948.
Takeyama, K., Tamaoki, J., Kondo, M., Isono, K., and Nagai, A. (2008). Role of epidermal growth factor receptor in maintaining airway goblet cell hyperplasia in rats sensitized to allergen. Clin Exp Allergy 38, 857-865.
Tesfaigzi, Y., Fischer, M.J., Martin, A.J., and Seagrave, J. (2000). Bcl-2 in LPS- and allergen-induced hyperplastic mucous cells in airway epithelia of Brown Norway rats. Am J Physiol Lung Cell Mol Physiol 279, L1210-L1217.
Turner, J., Roger, J., Fitau, J., Combe, D., Giddings, J., Heeke, G.V., and Jones, C.E. (2011). Goblet cells are derived from a FOXJ1-expressing progenitor in a human airway epithelium. Am J Resp Cell Mol Biol 44, 276-284.
Tyner, J.W., Kim, E.Y., Ide, K., Pelletier, M.R., Roswit, W.T., Morton, J.D., Battaile, J.T., Patel, A.C., Patterson, G.A., Castro, M., et al. (2006). Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-13 transdifferentiation signals. J Clin Invest 116, 309-321.
Van Hove, C.L., Maes, T., Cataldo, D.D., Guéders, M.M., Palmans, E., Joos, G.F., and Tournoy, K.G. (2009). Comparison of acute inflammatory and chronic structural asthma-like responses between C57BL/6 and BALB/c mice. Int Arch Allergy Immunol 149, 195-207.
Van Winkle, L.S., Isaac, J.M., and Plopper, C.G. (1997). Distribution of epidermal growth factor receptor and ligands during bronchiolar epithelial repair from naphthalene-induced Clara cell injury in the mouse. Am J Pathol 151, 443.
Walter, M.J., Morton, J.D., Kajiwara, N., Agapov, E., and Holtzman, M.J. (2002). Viral induction of a chronic asthma phenotype and genetic segregation from the acute response. J Clin Invest 110, 165-175.
Werley, M.S., Kirkpatrick, D.J., Oldham, M.J., Jerome, A.M., Langston, T.B., Lilly, P.D., Smith, D.C., and McKinney, W.J. (2016). Toxicological assessment of a prototype e-cigaret device and three flavor formulations: a 90-day inhalation study in rats. Inhal Toxicol 28, 22-38.
Wolf, D., Morgan, K., Gross, E., Barrow, C., Moss, O., James, R., and Popp, J. (1995). Two-year inhalation exposure of female and male B6C3F1 mice and F344 rats to chlorine gas induces lesions confined to the nose. Toxicol Sci 24, 111-131.
Yageta, Y., Ishii, Y., Morishima, Y., Ano, S., Ohtsuka, S., Matsuyama, M., Takeuchi, K., Itoh, K., Yamamoto, M., and Hizawa, N. (2014). Carbocisteine reduces virus-induced pulmonary inflammation in mice exposed to cigarette smoke. Am J Resp Cell Mol Biol 50, 963-973.