This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.
Increase, Mucin production leads to Hypersecretion, Mucus
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
Key Event Relationship Description
An increase in mucin production by goblet cells can lead to mucus hypersecretion in a disease context. Mucus hypersecretion occurs in obstructive airway diseases such as COPD, asthma, and cystic fibrosis. Excessive mucus is produced and plugging of airways can occur in small airways, leading to breathing difficulty.
Evidence Collection Strategy
Evidence Supporting this KER
It is biologically plausible that mucus production leads to mucus hypersecretion in a disease context. With sustained mucus production by cigarette smoke or other oxidants, a state of mucus hypersecretion can be reached, obstructing airways and leading to poor lung function. Mucus production can be stimulated by a variety of stimuli known to induce mucus hypersecretion including cigarette smoke or other oxidants (Shao et al., 2004; Takeyama et al., 2001; Yu et al., 2011; Casalino-Matsuda et al., 2009), including phorbol 12-myristate 13-acetate (PMA), 2,3,7,8-tetrachlorodibenzodioxin (TCDD), and sulfur dioxide (Hewson et al., 2004), (Lee et al., 2011), (Lamb and Reid, 1968) as well as bacteria (Dohrman et al., 1998; Hao et al., 2014)
Uncertainties and Inconsistencies
Mucus hypersecretion is not defined by a particular quantity, but is a feature of chronic bronchitis due to increased mucin production in a clinical sense. Increased mucus production and mucus hypersecretion is synonymous in animal studies.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Mucus production and hypersecretion has been well-documented in human, mouse and 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.
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.
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.