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Relationship: 1314


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

Chronic, Mucus hypersecretion leads to Decreased lung function

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

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
EGFR Activation Leading to Decreased Lung Function adjacent High Moderate 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 Do not cite Under Development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 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

Sex Applicability

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

Life Stage Applicability

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

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

Increased mucin production and mucus hypersecretion following acute exposure are thought to contribute to innate airway defenses and are most likely limited by anti-inflammatory mechanisms aimed at resolving the exposure-related stress (Rose and Voynow 2006; Ramos et al., 2014). However, under chronic exposure conditions, airway remodeling will persist, leading to airway narrowing, and the elevated number of goblet cells results in higher basal mucus levels (Rogers, 2007). Eventually, increased mucin production and mucus hypersecretion may lead to airway obstruction and a progressive decline in lung function over time (Kim and Criner, 2015; Aoshiba and Nagai, 2004; Vestbo et al, 1996). In the general population, the prevalence of chronic mucus hypersecretion is estimated to be between 3.5% to 12.7% (de Oca et al., 2012), and chronic mucus hypersecretion is linked to an excess decline of the forced expiratory volume in 1 s (FEV1) as well as increased hospitalization and mortality rates (Vestbo et al., 1989; Ekberg-Aronsson et al., 2005).

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
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

Clinical studies showed that MUC5AC expression in bronchial epithelium was inversely correlated with FEV1 (% predicted) and with FEV1/FVC ratio (Caramori et al., 2009; Innes et al., 2006), and epidemiological evidence indicates a link between mucus hypersecretion and decreased lung function (Allinson et al., 2015; Pistelli et al., 2003; Vestbo et al., 1996). As a cause-effect relationship between goblet cell hyperplasia/metaplasia, increased mucin production, mucus hypersecretion and airway obstruction cannot be conclusively proven, but the link between chronic mucus hypersecretion and lung function is clinically accepted, we believe that biological plausibility is high.

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

Mucus hypersecretion is a physiological response to inhalation exposures such as pollutants or infectious agents. As such, it is typically of short duration and does not pose a major problem to normal lung function. However, in the presence of chronic inflammation and goblet cell hyperplasia, increased mucus production may turn into mucus hypersecretion and ultimately decrease airflow. Because this may be accompanied by impaired mucociliary clearance and ineffective cough (Ramos et al., 2014), and owing to the lack of direct evidence, it is currently unclear whether chronic mucus hypersecretion alone is sufficient to elicit a decrease in lung function.

The prevalence of chronic mucus hypersecretion generally increases with age (Fletcher et al., 1976; Viegi et al., 2007). This may explain why Sunyer et al. (1998) did not observe decreased lung function in a randomly selected population of 20-45 year-old men and women that experienced occupational exposures to o dusts, gases, and fumes, even though those exposures were associated with a higher incidence of chronic phlegm in men exposed to mineral dust (relative risk, 1.94 [1.29–2.91]) and gases and fumes (relative risk, 1.53 [0.99–2.36]).

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

Allinson et al. (2015) reported that smoking cessation at any age reversed or avoided the escalating prevalence of smoking-related chronic mucus hypersecretion, similar to Kim et al. (2016) who found that quitting smoking increased the odds of "resolving" chronic bronchitis.

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

Following exposure to smoke from 3R4F research cigarettes for 1 h twice daily for 6 months (SCIREQ, InExpose model), ferrets developed goblet cell hyperplasia/metaplasia and chronic mucus hypersecretion (histology, PAS staining, Muc5b and Muc5ac staining). Mucus expression measured by PAS-positive goblet cell area, normalized by the size of the airway lumen to account for cell variation due to airway diameter, was 60% higher in smoke-exposed than in air-exposed animals (0.042% ± 0.025% smoke vs. 0.025% ± 0.013% air control). Inspiratory capacity, a sensitive marker of airway obstruction, was significantly reduced in smoke-exposed ferrets (79.5 ± 9.4 mL vs. 85.9 ± 5.9 mL air control) (Raju et al., 2016).

In a Dutch population-based cohort study, COPD subjects with chronic bronchitis (defined as having a productive cough for ⩾3 months a year during the past 2 years) had a 38.2 mL per year greater decline in FEV1 than COPD subjects without chronic bronchitis (95% CI −61.7 to−14.6 mL) adjusted for age, sex and pack-years of cigarette smoking (Lahousse et al., 2017).

In a  cross-sectional multicenter study in Belgium and Luxembourg, COPD patients with chronic bronchitis (defined as cough and sputum production for at least 3 months in each of two consecutive years, in the absence of other causes of chronic cough) had both lower FEV1% predicted and FEV1/VC% (Corhay et al., 2013). 

In the PLATINO study of 5,314 subjects (759 with and 4,554 without COPD), subjects with chronic bronchitis (defined as phlegm on most days, at least 3 months per year for >2 yrs) had worse lung function (pre-bronchodilator FEV1: 67.6 ± 2.10% predicted vs 81.0 ± 0.93; post-bronchodilator FEV1: 73.0 ± 2.10% predicted vs 84.0 ± 0.85; pre-bronchodilator FVC: 90.5 ± 2.18% predicted vs 99.6 ± 0.90; post-bronchodilator FVC: 96.0 ± 2.32% predicted vs 104.0±0.82) (de Oca et al., 2012).  

In the COPDgene study, COPD patients with chronic bronchitis had significantly lower FEV1% predicted and FVC% predicted than those without (63.20 ± 25.03 vs 79.91 ± 26.07 and 83.18 ± 17.44 vs 89.74 ± 18.12). They also experienced a greater annual decline in FEV1 than COPD patients without chronic bronchitis (-44.60 ± 61.58 mL vs -39.20 ± 49.42), although this was not significant (Kim et al., 2016).

In a Chinese study, COPD patients with chronic bronchitis (defined as the presence of cough and sputum production for at least 3 months in each of two consecutive years, in the absence of other causes of chronic cough) had lower FEV1% predicted and FVC% predicted than those without (42.1±18.0 vs 52.6±19.7 and 64.7±21.2 vs 75.1±24.2) (Liang et al., 2017).

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

In a 12-year follow-up study of 1,757 males and 2,191 females, men and women with chronic phlegm, a clinical surrogate of chronic mucus hypersecretion, showed a decline in FEV1 of 4.5±2.0 mL/year and 1.7±1.5 mL/year, respectively (Sherman et al., 1992).

In a 5-year follow-up study of 5,354 women and 4,081 men, chronic airway mucus hypersecretion was significantly associated with an excess decline in FEV1 decline of 22.8 mL/year and 12.6 mL/year among male and female COPD patients, respectively compared with men without airway mucus hypersecretion after adjusting for age, height, weight, and smoking (Vestbo et al., 1996).

An analysis of the National Survey of Health and Development (NSHD) data indicated that chronic mucus hypersecretion was associated with smoking status, and that the longer it was present, the faster was the decline in FEV1 (Allinson et al., 2015).

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


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

Allinson, J.P., Hardy, R., Donaldson, G.C., Shaheen, S.O., Kuh, D., and Wedzicha, J.A. (2016). The presence of chronic mucus hypersecretion across adult life in relation to chronic obstructive pulmonary disease development. Am. J. Respir. Crit. Care Med. 193, 662-672.

Aoshiba, K., and Nagai, A. (2004). Differences in airway remodeling between asthma and chronic obstructive pulmonary disease. Clin. Rev.  Allergy Immunol. 27, 35-43.

Caramori, G., Casolari, P., Di Gregorio, C., Saetta, M., Baraldo, S., Boschetto, P., Ito, K., Fabbri, L.M., Barnes, P.J., and Adcock, I.M. (2009). MUC5AC expression is increased in bronchial submucosal glands of stable COPD patients. Histopathology 55, 321-331.

Corhay, J.-L., Vincken, W., Schlesser, M., Bossuyt, P., and Imschoot, J. (2013). Chronic bronchitis in COPD patients is associated with increased risk of exacerbations: a cross‐sectional multicentre study. Int. J. Clin. Pract. 67, 1294-1301.

de Oca, M.M., Halbert, R.J., Lopez, M.V., Perez-Padilla, R., Tálamo, C., Moreno, D., et al. (2012). The chronic bronchitis phenotype in subjects with and without COPD: the PLATINO study. Eur. Respir. J. 40, 28-36. 

Ekberg-Aronsson, M., Pehrsson, K., Nilsson, J.-Å., Nilsson, P.M., and Löfdahl, C.-G. (2005). Mortality in GOLD stages of COPD and its dependence on symptoms of chronic bronchitis. Respir. Res. 6, 1-9.

Fletcher, C., Peto, R., Tinker, C., and Speizer, F.E. (1976). The natural history of chronic bronchitis and emphysema. An eight-year study of early chronic obstructive lung disease in working men in London. Oxford University Press, London. 

Innes, A.L., Woodruff, P.G., Ferrando, R.E., Donnelly, S., Dolganov, G.M., Lazarus, S.C., and Fahy, J.V. (2006). Epithelial mucin stores are increased in the large airways of smokers with airflow obstruction. Chest 130, 1102-1108.

Kim, V., and Criner, G.J. (2015). The chronic bronchitis phenotype in chronic obstructive pulmonary disease: features and implications. Curr. Opin. Pulm. Med. 21, 133-141.

Kim, V., Zhao, H., Boriek, A.M., Anzueto, A., Soler, X., Bhatt, S.P., et al. (2016). Persistent and newly developed chronic bronchitis are associated with worse outcomes in chronic obstructive pulmonary disease. Ann. Am. Thorac. Soc. 13, 1016-1025.

Lahousse, L., Seys, L.J., Joos, G.F., Franco, O.H., Stricker, B.H., and Brusselle, G.G. (2017). Epidemiology and impact of chronic bronchitis in chronic obstructive pulmonary disease. Eur. Respir. J. 50, 1602470.

Liang, Y., Chen, Y., Wu, R., Lu, M., Yao, W., Kang, J., et al. (2017). Chronic bronchitis is associated with severe exacerbation and prolonged recovery period in Chinese patients with COPD: a multicenter cross-sectional study. J. Thorac. Dis. 9, 5120-5130. 

Ma, R., Wang, Y., Cheng, G., Zhang, H., Wan, H., and Huang, S. (2005). MUC5AC expression up-regulation goblet cell hyperplasia in the airway of patients with chronic obstructive pulmonary disease. Chin. Med. Sci. J 20, 181-184.

Pistelli, R., Lange, P., and Miller, D.L. (2003). Determinants of prognosis of COPD in the elderly: mucus hypersecretion, infections, cardiovascular comorbidity. Eur. Resp. J. 21, 10s-14s.

Raju, S.V., Kim, H., Byzek, S.A., Tang, L.P., Trombley, J.E., Jackson, P., et al. (2016). A ferret model of COPD-related chronic bronchitis. JCI Insight 1, e87536.

Rogers, D.F. (2007). Physiology of airway mucus secretion and pathophysiology of hypersecretion. Respir. Care 52, 1134-1149.

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

Sherman, C.B., Xu, X., Speizer, F.E., Ferris, B.G., Jr., Weiss, S.T., and Dockery, D.W. (1992). Longitudinal lung function decline in subjects with respiratory symptoms. Am. Rev. Respir. Dis. 146, 855-859. 

Sunyer, J., Zock, J.P., Kromhout, H., Garcia-Esteban, R., Radon, K., Jarvis, D., et al. (2005). Lung function decline, chronic bronchitis, and occupational exposures in young adults. Am. J. Respir. Crit. Care Med. 172, 1139-1145.

Vestbo, J., and Rasmussen, F. (1989). Respiratory symptoms and FEV1 as predictors of hospitalization and medication in the following 12 years due to respiratory disease. Eur. Respir. J. 2, 710-715.

Vestbo, J., Prescott, E., and Lange, P. (1996). Association of chronic mucus hypersecretion with FEV1 decline and chronic obstructive pulmonary disease morbidity. Copenhagen City Heart Study Group. Am. J. Respir. Crit. Care Med. 153, 1530-1535.

Viegi, G., Pistelli, F., Sherrill, D.L., Maio, S., Baldacci, S., and Carrozzi, L. (2007). Definition, epidemiology and natural history of COPD. Eur. Respir. J. 30, 993-1013.