Upstream eventIncrease, Mucin production
Chronic, Mucus hypersecretion
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|EGFR Activation Leading to Decreased Lung Function||adjacent||High||Moderate|
Life Stage Applicability
Key Event Relationship Description
EGFR signaling is considered critical for mucus hypersecretion and goblet cell hyperplasia/metaplasia (Curran and Cohn, 2011), and numerous studies indicate that inhibition of EGFR results in a decrease of mucin production or goblet cell numbers (Tyner et al., 2006; Shim et al., 2001; Takeyama et al., 2008; Lee et al., 2011; Taniguchi et al., 2011; Song et al., 2016; Takeyama et al., 2001).
Evidence Supporting this KER
Activation of EGFR by oxidative stress was shown to correlate with increased mucin mRNA and protein expression, involving classical EGFR signal transduction via the MAPK cascade to activate the Sp-1 or, at least in mice, HIF-1α transcription factors that govern MUC5AC gene expression (Oyanagi et al., 2016; Di et al., 2012; Hewson et al., 2004; Lee et al., 2011; Perrais et al., 2002; Barbier et al., 2012). In addition, activation of EGFR can also downregulate FOXA2, a known transcriptional repressor of mucin genes, although the underlying mechanism is as of yet unknown (Hao et al., 2014; Zhen et al., 2007).
Studies in human airway epithelial cells, mice and in rats demonstrated that increased mucin production following infection with M. pneumonia and exposure to PM2.5, acrolein or cigarette smoke can be greatly diminished by (pre-)treatment with EGFR inhibitors or a neutralizing antibody preventing EGFR ligand binding (Casalino-Matsuda et al., 2006; Val et al., 2012; Takeyama et al., 2001; Lee et al., 2000; Hegab et al., 2007; Deshmukh et al., 2005; Deshmukh et al., 2008; Kim et al., 2010), supporting biological plausibility for this KER.
Exposure of H292 cells to fine particulate matter (PM2.5) increased production of the EGFR ligands amphiregulin and TGF-A in a dose- and time-dependent manner, and increasing concentrations of amphiregulin were shown to dose-dependently increase MUC5AC mRNA expression. The increase in MUC5AC mRNA levels could be prevented by co-treatment of H292 cells with the EGFR inhibitor AG1478 or a neutralizing EGFR antibody (Val et al., 2012).
In cigarette smoke extract-treated H292 cells, EGFR mRNA and protein phosphorylation were induced, which was accompanied by upregulation of MUC5AC gene expression. Both EGFR activation and the increase in MUC5AC mRNA levels could be prevented by pretreatement of the cells with AG1478 or BIBX1522 (Takeyama et al., 2001). Similarly, acrolein exposure of H292 cells increased EGFR phosphorylation and MUC5AC gene expression, both of which could be prevented by pretreatment of cells with AG1478 (Deshmukh et al., 2008).
Exposure of Sprague-Dawley rats to cigarette smoke caused increases in EGFR and MUC5AC gene expression levels as well as increased EGFR phosphorylation. Treatment with AG1478 prevented cigarette smoke-induced upregulation of MUC5AC mRNA, but not EGFR mRNA and completely abolished EGFR phosphorylation (Hegab et al., 2000).
Uncertainties and Inconsistencies
Mucin production can also be stimulated by other, concomitant oxidative stress-induced, but EGFR-independent, processes known to contribute to increased expression of mucins. For example, Gensch et al. (2004) reported MUC5AC upregulation in vitro and in vivo following cigarette smoke exposure and identified Src, ERK, JNK and AP-1 activation as critical steps in mediating ROS effects in human airway tissues in vitro, and Zhou et al. (2016) reported increased mucin expression in response to autophagy caused by cigarette smoke exposure in vitro and in vivo.
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Barbier, D., Garcia-Verdugo, I., Pothlichet, J., Khazen, R., Descamps, D., Rousseau, K., Thornton, D., Si-Tahar, M., Touqui, L., Chignard, M., et al. (2012). Influenza A induces the major secreted airway mucin MUC5AC in a protease–EGFR–extracellular regulated kinase–Sp1–dependent pathway. Am J Resp Cell Mol Biol 47, 149-157.
Casalino-Matsuda, S.M., Monzón, M.E., and Forteza, R.M. (2006). Epidermal growth factor receptor activation by epidermal growth factor mediates oxidant-induced goblet cell metaplasia in human airway epithelium. Am J Resp Cell Mol Biol 34, 581-591.
Curran, D.R., and Cohn, L. (2010). Advances in mucous cell metaplasia: a plug for mucus as a therapeutic focus in chronic airway disease. Am J Resp Cell Mol Biol 42, 268-275.
Deshmukh, H.S., Case, L.M., Wesselkamper, S.C., Borchers, M.T., Martin, L.D., Shertzer, H.G., Nadel, J.A., and Leikauf, G.D. (2005). Metalloproteinases mediate mucin 5AC expression by epidermal growth factor receptor activation. Am J Resp Crit Care Med 171, 305-314.
Deshmukh, H.S., Shaver, C., Case, L.M., Dietsch, M., Wesselkamper, S.C., Hardie, W.D., Korfhagen, T.R., Corradi, M., Nadel, J.A., and Borchers, M.T. (2008). Acrolein-activated matrix metalloproteinase 9 contributes to persistent mucin production. Am J Resp Cell Mol Biol 38, 446-454.
Di, Y.P., Zhao, J., and Harper, R. (2012). Cigarette smoke induces MUC5AC protein expression through the activation of Sp1. J Biol Chem 287, 27948-27958.
Gensch, E., Gallup, M., Sucher, A., Li, D., Gebremichael, A., Lemjabbar, H., Mengistab, A., Dasari, V., Hotchkiss, J., Harkema, J., et al. (2004). Tobacco smoke control of mucin production in lung cells requires oxygen radicals, AP-1 and JNK. J Biol Chem 279, 39085-39093.
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.
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.
Hewson, C.A., Edbrooke, M.R., and Johnston, S.L. (2004). PMA induces the MUC5AC respiratory mucin in human bronchial epithelial cells, via PKC, EGF/TGF-α, Ras/Raf, MEK, ERK and Sp1-dependent mechanisms. J Mol Biol 344, 683-695.
Kim, H.J., Ryu, J.-H., Kim, C.-H., Lim, J.W., Moon, U.Y., Lee, G.H., Lee, J.-G., Baek, S.J., and Yoon, J.-H. (2010). Epicatechin gallate suppresses oxidative stress–induced MUC5AC overexpression by interaction with epidermal growth factor receptor. Am J Resp Cell Mol Biol 43, 349-357.
Lee, H.-M., Takeyama, K., Dabbagh, K., Lausier, J.A., Ueki, I.F., and Nadel, J.A. (2000). Agarose plug instillation causes goblet cell metaplasia by activating EGF receptors in rat airways. Am J Physiol Lung Cell Mol Physiol 278, L185-L192.
Lee, Y.C., Oslund, K.L., Thai, P., Velichko, S., Fujisawa, T., Duong, T., Denison, M.S., and Wu, R. (2011). 2,3,7,8-Tetrachlorodibenzo-p-dioxin–induced MUC5AC expression aryl hydrocarbon receptor-independent/EGFR/ERK/p38-dependent SP1-based transcription. Am J Resp Cell Mol Biol 45, 270-276.
Oyanagi, T., Takizawa, T., Aizawa, A., Solongo, O., Yagi, H., Nishida, Y., Koyama, H., Saitoh, A., and Arakawa, H. (2017). Suppression of MUC5AC expression in human bronchial epithelial cells by interferon-γ. Allergol Int 66, 75-82.
Perrais, M., Pigny, P., Copin, M.C., Aubert, J.P., and Van Seuningen, I. (2002). Induction of MUC2 and MUC5AC mucins by factors of the epidermal growth factor (EGF) family is mediated by EGF receptor/Ras/Raf/extracellular signal-regulated kinase cascade and Sp1. J Biol Chem 277, 32258-32267.
Shim, J.J., Dabbagh, K., Ueki, I.F., Dao-Pick, T., Burgel, P.R., Takeyama, K., Tam, D.C.W., and Nadel, J.A. (2001). IL-13 induces mucin production by stimulating epidermal growth factor receptors and by activating neutrophils. Am J Physiol Lung Cell Mol Physiol 280, L134-140.
Song, L., Tang, H., Liu, D., Song, J., Wu, Y., Qu, S., and Li, Y. (2016). The chronic and short-term effects of gefinitib on airway remodeling and inflammation in a mouse model of asthma. Cell Physiol Biochem 38, 194-206.
Takeyama, K., Jung, B., Shim, J.J., Burgel, P.-R., Dao-Pick, T., Ueki, I.F., Protin, U., Kroschel, P., and Nadel, J.A. (2001). Activation of epidermal growth factor receptors is responsible for mucin synthesis induced by cigarette smoke. Am J Physiol Lung Cell Mol Physiol 280, L165-L172.
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.
Taniguchi, K., Yamamoto, S., Aoki, S., Toda, S., Izuhara, K., and Hamasaki, Y. (2011). Epigen is induced during the interleukin-13–stimulated cell proliferation in murine primary airway epithelial cells. Exp Lung Res 37, 461-470.
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.
Val, S., Belade, E., George, I., Boczkowski, J., and Baeza-Squiban, A. (2012). Fine PM induce airway MUC5AC expression through the autocrine effect of amphiregulin. Arch Toxicol 86, 1851-1859.
Zhen, G., Park, S.W., Nguyenvu, L.T., Rodriguez, M.W., Barbeau, R., Paquet, A.C., and Erle, D.J. (2007). IL-13 and epidermal growth factor receptor have critical but distinct roles in epithelial cell mucin production. Am J Resp Cell Mol Biol 36, 244-253.
Zhou, J.-S., Zhao, Y., Zhou, H.-B., Wang, Y., Wu, Y.-F., Li, Z.-Y., Xuan, N.-X., Zhang, C., Hua, W., Ying, S.-M., et al. (2016). Autophagy plays an essential role in cigarette smoke-induced expression of MUC5AC in airway epithelium. Am J Physiol Lung Cell Mol Physiol 310, L1042-L1052.