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Event: 962

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Increase, Mucin production

Short name

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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Cell term
goblet cell

Organ term

Organ term
lung

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
gene expression	mucin-5AC	increased
translation	mucin-5AC	increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Decreased lung function	KeyEvent	Karsta Luettich (send email)	Under development: Not open for comment. Do not cite	Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
human	Homo sapiens	High	NCBI
mouse	Mus musculus	High	NCBI
rat	Rattus norvegicus	High	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
Adult	High

Sex Applicability

An indication of the the relevant sex for this KE. More help

Term	Evidence
Mixed	High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

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

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

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

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

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).

References

List of the literature that was cited for this KE description. More help

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.

Bhattacharyya, S.N., Dubick, M.A., Yantis, L.D., Enriquez, J.I., Buchanan, K.C., Batra, S.K., et al. (2004). In vivo effect of wood smoke on the expression of two mucin genes in rat airways. Inflammation 28, 67-76.

Borchers, M.T., Wert, S.E., and Leikauf, G.D. (1998). Acrolein-induced MUC5ac expression in rat airways. Am. J. Physiol. Lung Cell. Mol. Physiol. 274, L573-L581.

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.

Chen, P., Deng, Z., Wang, T., Chen, L., Li, J., Feng, Y., et al. (2013). The potential interaction of MARCKS-related peptide and diltiazem on acrolin-induced airway mucus hypersecretion in rats. Int. Immunopharmacol. 17, 625-632.

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.

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.

Kato, K., Chang, E.H., Chen, Y., Lu, W., Kim, M.M., Niihori, M., et al. (2020). MUC1 contributes to goblet cell metaplasia and MUC5AC expression in response to cigarette smoke in vivo. Am. J. Physiol. Lung Cell. Mol. Physiol. 319, L82-L90.

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, S.Y., Kang, E.J., Hur, G.Y., Jung, K.H., Jung, H.C., Lee, S.Y., et al. (2006). The inhibitory effects of rebamipide on cigarette smoke-induced airway mucin production. Respir. Med. 100, 503-511.

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.

Liu, D.-S., Liu, W.-J., Chen, L., Ou, X.-M., Wang, T., Feng, Y.-L., et al. (2009). Rosiglitazone, a peroxisome proliferator-activated receptor-γ agonist, attenuates acrolein-induced airway mucus hypersecretion in rats. Toxicology 260, 112-119.

Montalbano, A.M., Albano, G.D., Anzalone, G., Bonanno, A., Riccobono, L., Di Sano, C., et al. (2014). Cigarette smoke alters non-neuronal cholinergic system components inducing MUC5AC production in the H292 cell line. Eur. J. Pharmacol. 736, 35-43.

Nadel, J.A. (2013). Mucous hypersecretion and relationship to cough. Pulm. Pharmacol. Therap. 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).

Wagner, J. G., Van Dyken, S. J., Wierenga, J. R., Hotchkiss, J. A., & 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.

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.

Yu, H., Li, Q., Kolosov, V.P., Perelman, J.M., and Zhou, X. (2012). Regulation of cigarette smoke‐mediated mucin expression by hypoxia‐inducible factor‐1α via epidermal growth factor receptor‐mediated signaling pathways. J. Appl. Toxicol. 32, 282-292.

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.