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Relationship: 1315


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increase, Mucin production leads to Chronic, Mucus hypersecretion

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
mouse Mus musculus Moderate NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Mixed Moderate

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Adult Low

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Chronic mucus hypersecretion, i.e., the sustained production of mucus, is a main feature of chronic lung diseases. The presence of goblet cell hyperplasia or goblet cell metaplasia in the lungs of chronic obstructive pulmonary disease, asthma and cystic fibrosis patients has been inferred as cause for sustained mucus production, because the increased number (or increased size) of goblet cells is associated with an increase in the volume of mucus produced (Jackson, 2001; Innes et a. 2006; Rose and Voynow, 2006; Munkholm and Mortensen, 2014). 

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Mucus hypersecretion is a feature of animal models of asthma (Shim et al., 2001; Singer et al., 2004; Song et al., 2016) and occurs in mice and rats following inhalation of e.g. acrolein and cigarette smoke (Deshmukh et al., 2008; Yang et al., 2012; Chen et al., 2013; Vlahos and Bozinovski, 2014; Liu et al., 2017). There appears to be no consensus as to the "chronicity" of mucus hypersecretion, and because there are no standardized measures of mucus hypersecretion, experimental evidence is limited. Clinically, (chronic) mucus hypersecretion is defined as coughing and sputum production for >3 months in at least two consecutive years and called "chronic bronchitis" (Vestbo, 2002). Long-term smokers with and without airflow obstruction present with chronic mucus hypersecretion and increased mucin production (O'Donnell et al., 2004; Caramori et al., 2004; Innes et al., 2006; Kim et al., 2008).

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

Chronic mucus hypersecretion, i.e., the sustained production of mucus, is the key symptom of COPD and asthma, and is also observed in patients with bronchiectasis and cystic fibrosis. To a certain extent, it can also be modeled in animals as has been shown in mouse models of asthma. We therefore consider this KER to be biologically plausible with moderate confidence.

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Caramori et al. (2009) found no correlation between MUC5AC immunostaining and the presence of chronic bronchitis. Kim et al. (2015) reported higher goblet cell numbers and mucin volume density in healthy smokers than in COPD patients and also no difference in mucin volume density between smokers with and without chronic bronchitis.

In some instances, sputum or phlegm production/output may have been considered quantitative evidence for chronic mucus hypersecretion. However, Danahay and Jackson (2005) noted that "[sputum] represents an indirect measure of the contribution that mucus makes to that part of the airway secretions that is amenable to clearance. It is possible that the bulk of the disease modifying potential of the mucus-hypersecretory phenotype does not directly relate to cleared mucus/sputum..."

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help


Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

There was a marked increase in MUC5AC immunostaining in the bronchial epithelium of smokers compared to nonsmokers, and there was a significant correlation between % MUC5AC-stained epithelial area and the numbers of epithelial cells staining positively for both MUC5AC and PAS (O'Donnell et al., 2004).

In the bronchiolar epithelium, intraluminal AB/PAS staining was significantly more frequent among COPD subjects than smokers or never-smokers (1 ⁄ 6, 2 ⁄ 11 and 7 ⁄ 9 in never-smokers, smokers and COPD subjects). MUC5AC expression was also significantly higher in COPD subjects compared with smokers and never-smokers (score [0 indicating absence of staining, 1 indicating a staining limited to cilia, 2 indicating supranuclear cytoplasmic staining, 3 indicating supranuclear cytoplasmic staining and staining of goblet cells]: 2 (1–2.3) in COPD vs 0 (0–1) in never-smokers and 0.5 (0–1) in smokers) (Caramori et al., 2009).

In a small study of 24 cigarette smokers and 19 non-smoking control subjects, the goblet cell number per surface area of basal lamina in the large airways was 80% higher in smokers (56,232 + 5611 vs 41,996 + 4610), with a 30% higher mean volume of individual goblet cells ( 2,925 + 173 µm3 vs 2,259 + 192 µm3) than in non-smokers. MUC5AC immunostaining in the surface airway epithelium was also 80% higher in smokers than in control subjects (volume of epithelial MUC5AC per surface area of basal lamina: 6.82 + 0.98 µm3/µm2 vs 3.70 + 0.69 µm3/µm2) (Innes et al., 2006).

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help


Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help


Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Mucus hypersecretion occurs in mice and rats (Shim et al., 2001; Singer et al., 2004; Song et al., 2016; Deshmukh et al., 2008; Yang et al., 2012; Chen et al., 2013; Vlahos and Bozinovski, 2014; Liu et al., 2017) and in humans (Vestbo, 2002; O'Donnell et al., 2004; Caramori et al., 2004; Innes et al., 2006; Kim et al., 2008).


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

Caramori, G., Casolari, P., Di Gregorio, C., Saetta, M., Baraldo, S., Boschetto, P., et al. (2009). MUC5AC expression is increased in bronchial submucosal glands of stable COPD patients. Histopathology 55, 321-331.

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.

Danahay, H., and Jackson, A.D. (2005). Epithelial mucus-hypersecretion and respiratory disease. Curr. Drug Targets Inflamm. Allergy 4, 651-664.

Deshmukh, H.S., Shaver, C., Case, L.M., Dietsch, M., Wesselkamper, S.C., Hardie, W.D., et al. (2008). Acrolein-activated matrix metalloproteinase 9 contributes to persistent mucin production. Am. J. Respir. Cell Mol. Biol. 38, 446-454.

Jackson, A.D. (2001). Airway goblet-cell mucus secretion. Trends Pharmacol. Sci. 22, 39-45.

Kim, V., Kelemen, S.E., Abuel-Haija, M., Gaughan, J.P., Sharafkaneh, A., Evans, C.M., et al. (2008). Small airway mucous metaplasia and inflammation in chronic obstructive pulmonary disease. COPD 5, 329-338.

Kim, V., Oros, M., Durra, H., Kelsen, S., Aksoy, M., Cornwell, W.D., et al. (2015). Chronic Bronchitis and Current Smoking Are Associated with More Goblet Cells in Moderate to Severe COPD and Smokers without Airflow Obstruction. PLoS ONE 10, e0116108. 

Liu, Z., Geng, W., Jiang, C., Zhao, S., Liu, Y., Zhang, Y., et al. (2017). Hydrogen-rich saline inhibits tobacco smoke-induced chronic obstructive pulmonary disease by alleviating airway inflammation and mucus hypersecretion in rats. Exp. Biol. Med. 242, 1534-1541. 

Munkholm, M., and Mortensen, J. (2014). Mucociliary clearance: pathophysiological aspects. Clin. Physiol. Funct. Imaging 34, 171-177.

O’Donnell, R., Richter, A., Ward, J., Angco, G., Mehta, A., Rousseau, K., et al. (2004). Expression of ErbB receptors and mucins in the airways of long term current smokers. Thorax 59, 1032-1040.

Rose, M.C., and Voynow, J.A. (2006). Respiratory tract mucin genes and mucin glycoproteins in health and disease. Physiol. Rev. 86, 245-278. 

Shim, J.J., Dabbagh, K., Ueki, I.F., Dao-Pick, T., Burgel, P.R., Takeyama, K., et al. (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.

Singer, M., Martin, L.D., Vargaftig, B.B., Park, J., Gruber, A.D., Li, Y., et al. (2004). A MARCKS-related peptide blocks mucus hypersecretion in a mouse model of asthma. Nat. Med. 10, 193-196.

Song, L., Tang, H., Liu, D., Song, J., Wu, Y., Qu, S., et al. (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.

Vestbo, J. (2002). Epidemiological studies in mucus hypersecretion. Novartis Found. Symp. 248, 3-12; discussion: 12-19, 277-282.

Vlahos, R., and Bozinovski, S. (2014). Recent advances in pre-clinical mouse models of COPD. Clin. Sci. 126, 253-265. 

Yang, T., Luo, F., Shen, Y., An, J., Li, X., Liu, X., et al. (2012). Quercetin attenuates airway inflammation and mucus production induced by cigarette smoke in rats. Int. Immunopharmacol. 13, 73-81.