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Key Event Title
Occurrence, Metaplasia of goblet cells
Key Event Components
Key Event Overview
AOPs Including This Key Event
Key Event Description
Metaplasia is the replacement of a differentiated cell type with another differentiated cell type. In the case of goblet cell metaplasia, ciliated or club cells transdifferentiate into goblet cells (Tyner et al., 2006; Evans et al., 2004), leading to an increased number of mucus-producing cells and eventually mucus hypersecretion. This adaptive change in the small airway epithelium, where goblet cells are typically sparse, is often observed following exposure to respiratory irritants including ozone, endotoxin and cigarette smoke (Harkema and Hotchkiss, 1993; Harkema and Wagner, 2002; Mebratu et al., 2011).
How It Is Measured or Detected
In vitro and in vivo studies assess metaplasia by looking for co-expression of cell markers or characteristics of two cell types though to be goblet cell progenitors, i.e. the club cell and the ciliated cell. CC-10/CSSP is commonly used as a club cell marker (Reader et al., 2003; Hayashi et al., 2004; Evans et al., 2004), while FOXJ1, beta-tubulin, tektin and DNAH9 were used as ciliated markers (Yoshisue and Hasegawa, 2004; Gomperts et al. 2007; Turner et al., 2011; Fujisawa et al., 2008). Apical localization of ezrin, ciliary beat frequency and glutamylated tubulins are other characteristics of ciliated cells (Laoukili et al., 2001). Transdifferentiation and metaplasia are said to occur when these ciliated cell characteristics and markers decrease, while expression of goblet cell markers such as MUC5AC and other mucin proteins increases. Light or fluorescence microscopy is used to show co-expression of markers and a transitory cell type (observation of goblet and cilia cell features within the same cell) (Tyner et al., 2006; Laoukili et al., 2001; Gomperts et al., 2007).
Goblet cell metaplasia is characterized by the presence of goblet cells (above the normal number; see above) in the epithelium lining the bronchi or bronchioles (Renne et al., 2009). In clinical samples, a pathologist may determine absence/presence of metaplasia. This assessment is not standardized, but based on experience, and may be semiquantitative if a score is assigned in relation to the extent of the finding.
Domain of Applicability
Goblet cell metaplasia has been observed in human (Gomperts et al. 2007; Laoukili et al., 2001; Yoshisue and Hasegawa, 2004; Turner et al., 2011; Casalino-Matsuda et al., 2006) and in mouse lungs (Fujisawa et al., 2008; Tyner et al., 2006). Studies in rat have not directly measured transdifferentiation of ciliated to goblet cells. However, airway remodeling of small airway epithelium with nearly no goblet cells to an epithelium with numerous goblet cells was observed (Harkema and Hotchkiss, 1993).
Evidence for Perturbation by Stressor
In female Han Wistar rats exposed to the smoke of 24 cigarettes (1R1; University of Kentucky) per day, for four consecutive days and treated with 20 µg LPS 24 h after the first exposure, increased AB/PAS staining in the large and smaller airways indicated goblet cell metaplasia (Baginski et al., 2006).
The number of AB-PAS positive cells in the lungs of male Sprague-Dawley rats exposed to smoke of 20 commercial unfiltered cigarettes for 30 min twice a day, for a total of four weeks was significantly increased (Jun et al., 2011).
Intranasal instillation with 2 or 20 µg endotoxin (150 µL/ nasal passage), followed by exposure to 1 ppm ozone for 8h (6 h after instillation) on 2 consecutive days caused goblet cell metaplasia in the axial pulmonary airways of F344 rats in a dose-dependent manner (Wagner et al., 2003).
Exposure of ovalbumin-sensitized Balb/c mice to 100 or 250 ppb ozone for 3 h caused goblet cell metaplasia in bronchi and bronchioles and significantly increased the number of PAS-positive cells (Larsen et al., 2010).
Exposure of Kunming mice to 4 ppm acrolein (nebulized) for 6 h per day, for up to 21 days caused goblet cell metaplasia and a significant increase in the area of AB-PAS positive staining in the small airways (Liu et al., 2009).
Exposure of Sprague–Dawley rats to 3 ppm acrolein for 3 h a day, 7 days a week, for 2 or 4 weeks caused goblet cell metaplasia and a time-dependent increase in the ratio of AB/PAS-positively staining area to total epithelial area in the airways (Wang et al., 2009).
Baginski, T.K., Dabbagh, K., Satjawatcharaphong, C., and Swinney, D.C. (2006). Cigarette smoke synergistically enhances respiratory mucin induction by proinflammatory stimuli. Am. J. Respir. Cell Mol. Biol. 35, 165-174.
Casalino-Matsuda, S., Monzón, M., and Forteza, R. (2006). Epidermal Growth Factor Receptor Activation by Epidermal Growth Factor Mediates Oxidant-Induced Goblet Cell Metaplasia in Human Airway Epithelium. Am. J. Respir. Cell Mol. Biol. 34, 581–591.
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. Respir. Cell Mol. Biol. 31, 382–394.
Fujisawa, T., Ide, K., Holtzman, M.J., Suda, T., Suzuki, K., Kuroishi, S., Chida, K., and Nakamura, H. (2008). Involvement of the p38 MAPK pathway in IL-13-induced mucous cell metaplasia in mouse tracheal epithelial cells. Respirol. 13, 191–202.
Gomperts, B.N., Kim, L.J., Flaherty, S.A., and Hackett, B.P. (2007). IL-13 regulates cilia loss and foxj1 expression in human airway epithelium. Am. J. Respir. Cell Mol. Biol. 37, 339-346.
Harkema, J., and Hotchkiss, J. (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.
Harkema, J., and Wagner, J. (2002). Non-allergic models of mucous cell metaplasia and mucus hypersecretion in rat nasal and pulmonary airways. Novartis Found. Symp. 248, 181–197; discussion 197–200, 277–282.
Hayashi, T., Ishii, A., Nakai, S., and Hasegawa, K. (2004). Ultrastructure of goblet-cell metaplasia from Clara cell in the allergic asthmatic airway inflammation in a mouse model of asthma in vivo. Virchows Arch. Int. J. Pathol. 444, 66–73.
Jun, X., Ke, W., Feng, Y.-l., Chen, X.-r., Dan, X., and Zhang, M.-k. (2011). Role of extracellular signal-regulated kinase 1/2 in cigarette smoke-induced mucus hypersecretion in a rat model. Chin. Med. J. 124, 3327-3333.
Laoukili, J., Perret, E., Willems, T., Minty, A., Parthoens, E., Houcine, O., Coste, A., Jorissen, M., Marano, F., Caput, D., et al. (2001). IL-13 alters mucociliary differentiation and ciliary beating of human respiratory epithelial cells. J. Clin. Invest. 108, 1817–1824.
Larsen, S.r.T., Matsubara, S., McConville, G., Poulsen, S.S., and Gelfand, E.W. (2010). Ozone increases airway hyperreactivity and mucus hyperproduction in mice previously exposed to allergen. J. Toxicol. Environm. Health A 73, 738-747.
Liu, D.-S., Wang, T., Han, S.-X., Dong, J.-J., Liao, Z.-L., He, G.-M., et al. (2009). p38 MAPK and MMP-9 cooperatively regulate mucus overproduction in mice exposed to acrolein fog. Int. Immunopharmacol. 9, 1228-1235.
Mebratu, Y.A., Schwalm, K., Smith, K.R., Schuyler, M., and Tesfaigzi, Y. (2011). Cigarette Smoke Suppresses Bik To Cause Epithelial Cell Hyperplasia and Mucous Cell Metaplasia. Am. J. Respir. Crit. Care Med. 183, 1531-1538.
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.
Renne, R., Brix, A., Harkema, J., Herbert, R., Kittel, B., Lewis, D., et al. (2009). Proliferative and nonproliferative lesions of the rat and mouse respiratory tract. Toxicol. Pathol. 37, Suppl. 7, 5s-73s.
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. Respir. Cell Mol. Biol. 44, 276–284.
Tyner, J., Tyner, E., Ide, K., Pelletier, M., Roswit, W., Morton, J., Battaile, J., Patel, A., Patterson, G., 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.
Wagner, J.G., Van Dyken, S.J., Wierenga, J.R., Hotchkiss, J.A., and Harkema, J.R. (2003). Ozone exposure enhances endotoxin-induced mucous cell metaplasia in rat pulmonary airways. Toxicol. Sci. 74, 437-446.
Wang, T., Liu, Y., Chen, L., Wang, X., Hu, X.-R., Feng, Y.-L., et al. (2009). Effect of sildenafil on acrolein-induced airway inflammation and mucus production in rats. Eur. Resp. J. 33, 1122-1132.
Yoshisue, H., and Hasegawa, K. (2004). Effect of MMP/ADAM inhibitors on goblet cell hyperplasia in cultured human bronchial epithelial cells. Biosci. Biotechnol. Biochem. 68, 2024–2031.