Key Event Title
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Decreased lung function||KeyEvent|
Key Event Description
Mucin production in healthy airway provides an important role in trapping and removing bacterial and viral pathogens and particulates. The major gel-forming mucins of the airways, MUC5AC and MUC5AB, are primarily involved in this function (Lillehoj et al., 2013). Various stimuli increase mucin production by goblet cells including cigarette smoke, phorbol 12-myristate 13-acetate (PMA), 2,3,7,8-tetrachlorodibenzodioxin (TCDD), ozone, acrolein, and sulfur dioxide (Lamb and Reid, 1968; Shao et al., 2004; Takeyama et al., 2001; Yu et al., 2011; Casalino-Matsuda et al., 2009; Hewson et al., 2004; Lee et al., 2011; Wagner et al., 2003) as well as bacteria and viruses (Dohrman et al., 1998; Hao et al., 2014; Zhu et al., 2009). Many of these stimuli specifically induce MUC5AC mRNA and protein production through activation of the EGFR pathway (Nadel, 2013). However, other signaling pathways, not necessarily requiring EGFR activation, via STAT6, FOXA2, SPDEF or NFkB have also been implicated in MUC5AC overexpression (reviewed by Turner and Jones, 2009).
How It Is Measured or Detected
To our knowledge, no validated method for the determination of mucin overproduction exists. In the literature, increased mucin production is frequently equated with increased MUC5AC mRNA and protein expression and much less frequently with changes in MUC5AB mRNA and protein levels.
Alterations in MUC5AC mRNA expression in cell and tissue lysates are commonly assessed by RT-PCR or RT-qPCR, whereas Northern blotting is less frequently used. Changes in MUC5AC protein levels can be detected by ELISA or Western blot in cell and tissue lysates and secretions or by immunocyto/histochemistry/immunofluorescence in cytological preparations or histological tissue sections with an appropriate antibody. It is worth noting here that some antibodies are not suitable for ELISA or Western blot, because extensive glycosylation of mucins may mask epitopes or block access of the antibody to the epitope (Rose and Voynow, 2006). Alternatively, labeled and label-free mass spectrometry-based approaches could be utilized for targeted identification of mucins and their quantification in cell and tissue samples. For in vivo studies and clinical samples, an experienced pathologist may judge the presence and severity of mucin production on histological tissue sections stained with hematoxylin/eosin and Alcian blue and/or periodic acid Schiff stains. A grading or scoring system may enable semi-quantitative assessment, but remains subjective at best since corresponding standards are currently lacking.
Domain of Applicability
The MUC5AC gene is conserved in Rhesus monkey, dog, cow, mouse, rat, zebrafish, and frog, and the MUC5B gene is conserved in dog, mouse, rat, and chicken. Evidence in support of this KE primarily derives from in vitro studies with human cell systems, while corroborating in vivo evidence comes from studies in small rodents (mouse or rat).
Casalino-Matsuda, S., Monzon, M., Day, A., and Forteza, R. (2009). Hyaluronan fragments/CD44 mediate oxidative stress-induced MUC5B up-regulation in airway epithelium. Am J Respir Cell Mol Biol 40, 277–285.
Dohrman, A., Miyata, S., Gallup, M., Li, J.D., Chapelin, C., Coste, A., Escudier, E., Nadel, J., and Basbaum, C. (1998). Mucin gene (MUC 2 and MUC 5AC) upregulation by Gram-positive and Gram-negative bacteria. Biochim Biophys Acta 1406, 251–259.
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.
Hewson, C., Edbrooke, M., and Johnston, S. (2004). PMA induces the MUC5AC respiratory mucin in human bronchial epithelial cells, via PKC, EGF/TGF-alpha, Ras/Raf, MEK, ERK and Sp1-dependent mechanisms. J Mol Biol 344, 683–695.
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.
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. Am J Respir Cell Mol Biol 45, 270–276.
Lillehoj, E. P., Kato, K., Lu, W., & Kim, K. C. (2013). Cellular and Molecular Biology of Airway Mucins. Int Rev Cell Mol Biol, 303, 139–202.
Nadel, J.A. (2013). Mucous hypersecretion and relationship to cough. Pulmonary Pharmacology & Therapeutics 26, 510-513.
Rose, M.C., and Voynow, J.A. (2006). Respiratory tract mucin genes and mucin glycoproteins in health and disease. Physiol Rev 86, 245-278.
Shao, M., Nakanaga, T., and Nadel, J. (2004). Cigarette smoke induces MUC5AC mucin overproduction via tumor necrosis factor-alpha-converting enzyme in human airway epithelial (NCI-H292) cells. Am J Physiol Lung Cell Mol Physiol 287, L420–L427.
Takeyama, K., Jung, B., Shim, J., Burgerl, P., Dao-Pick, T., Ueki, I., Protin, U., Kroschel, P., and Nadel, J. (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.
Turner, J., and Jones, C.E. (2009). Regulation of mucin expression in respiratory diseases (Portland Press Limited).
Yu, H., Li, Q., Zhou, X., Kolosov, V., and Perelman, J. (2011). Role of hyaluronan and CD44 in reactive oxygen species-induced mucus hypersecretion. Mol Cell Biochem 352, 65–75.
Zhu, L., Lee, P., Lee, W., Zhao, Y., Yu, D., & Chen, Y. (2009). Rhinovirus-Induced Major Airway Mucin Production Involves a Novel TLR3-EGFR–Dependent Pathway. Am J Resp Cell Mol Biol 40, 610–619.