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Event: 1251

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Chronic, Mucus hypersecretion

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. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.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. More help

Organ term
lung

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). 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 signalling 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. More help

Process	Object	Action
mucus secretion	lung goblet cell	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

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Name
Cigarette smoke
PM10
Nitric oxide

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. 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	Moderate	NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help

Life stage	Evidence
Adult	Moderate

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help

Term	Evidence
Mixed	Moderate

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. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

Mucus hypersecretion is a physiological response to inhalation exposures to pollutants or infectious agents. As such, it is typically of short duration and does not pose a major problem to normal lung function. Under chronic stress/exposure conditions, airway remodeling and mucus hypersecretion will cease being a physiological stress response aimed at eliminating the potential hazard and regaining the balance of a healthy airway epithelium, and chronic mucus hypersecretion will ensue. This is the case in many respiratory diseases that feature a chronic inflammatory micoenvironment such as chronic obstructive pulmonary disease and asthma (Evans et al., 2009; Allinson et al., 2016). Recent estimates of chronic mucus hypersecretion in the global population range from 3.5 to 27% (Kim et al. 2011; Martinez et al. 2014; Montes De Oca et al. 2012).

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. 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).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

To our knowledge, there is no report regarding the assessment of chronic mucus hypersecretion in vitro. This is most likely related to the fact that many in vitro studies are of short duration, employing acute exposures to mucus-inducing stimuli. However, 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, 2015; Liu et al., 2017). There appears to be no consensus as to the "chronicity" of mucus hypersecretion, and no standardized measure exists.

Clinically, coughing and sputum production for >3 months in at least two consecutive years is defined as (chronic) mucus hypersecretion (Vestbo, 2002). More recently, questionnaires such as the St George’s Respiratory Questionnaire (Hardin and Rennard, 2015), the COPD Assessment Test (CAT) (Stott-Miller et al., 2020) and the American Thoracic Society Questionnaire (Cassidy et al., 2015) have been employed to evaluate cough and sputum production, and hence mucus hypersecretion. At times, sputum volumes are recorded as measure of mucus production. Current clinical practice, however, does not include a quantitative measure of mucus hypersecretion.

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information. More help

Mucus hypersecretion was described in mice and rats following ovalbumin challenge (Shim et al., 2001; Singer et al., 2004; Song et al., 2016) or exposure to acrolein and cigarette smoke (Deshmukh et al., 2008; Yang et al., 2012; Chen et al., 2013; Vlahos and Bozinovski, 2015; Liu et al., 2017). Chronic mucus hypersecretion is also frequently found in long-term smokers, COPD patients with chronic bronchitis and asthma patients (Danahay and Jackson, 2005).

Evidence for Perturbation by Stressor

Cigarette smoke

Smokers had a higher mucus volume density than non-smokers (27.78 ± 10.24 μL/mm² vs 3.42 ± 3.07 μL/mm²) (Kim et al., 2015).

A cross-sectional study in twins indicated that smoking was a risk factor for chronic mucus hypersecretion, and there was a dose-response relationship between daily tobacco consumption and prevalence of chronic mucus hypersecretion (Harmsen et al., 2010). A dose-response relationship between chronic mucus hypersecretion and pack-years of smoking was also observed in the Dutch LifeLines cohort study. This study additionally highlighted that exposure to environmental cigarette smoke ("seond-hand smoke") was also associated with the risk of chronic mucus hypersecretion (Dijkstra et al., 2014).

PM10

A statistically significant positive association was seen between prevalent chronic bronchitis, defined as chronic cough productive of phlegm for at least 3 months out of a year for a minimum of 2 consecutive years, and PM10 [estimated median exposure concentration: 2.16 μg/m³ (interquartile range: 5.8 μg/m³); odds ratio (OR) per IQR increase in PM10 = 1.07; 95% confidence interval (CI): 1.01, 1.13] and chronic phlegm (OR = 1.07; 95% CI: 1.02, 1.11) in the NIEHS Sister Study (Hooper et al., 2018).

The SAPALDIA study observed that an increase of 10 mg/m³ in PM10 levels was associated with an increase in the prevalence of chronic phlegm, and chronic cough or phlegm. Within the range of 10.1 to 33.4 mg/m³ PM10, the OR for an increase of 10 mg/m³ in the annual mean was 1.35 (CI: 1.11 to 1.65) for chronic phlegm among never-smokers and 1.27(CI: 1.08 to 1.50) for chronic cough or phlegm (Zemp et al., 1999).

Nonsmoking women cooking with wood stoves reported chronic phlegm more frequently than those cooking with gas stoves. The peak indoor concentration of particulate matter (PM10) often exceeded 2 mg/m³(Regalado et al., 2006).

Nonsmokers who experienced several years of many days per year when PM10 exceeded 80 pg/m³developed chronic productive cough and overall chronic bronchitis significantly more frequently than those not exposed to PM10 concentrations below this cut-off (Abbey et al., 1998).

Nitric oxide

At the individual level, self‐reported traffic intensity and home outdoor levels of NO₂ (a surrogate of traffic exposure) were associated with frequency of chronic phlegm in females, independent of smoking (Sunyer et al., 2006).

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help

Abbey, D.E., Nishino, N., and McDonnell, W.F. (1998). Development of chronic productive cough as associated with long-term ambient inhalable particulate pollutants (PM10) in nonsmoking adults: the AHSMOG study. Appl. Occup. Environ. Hyg. 13, 444-452.

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. Resp. Crit. Care Med. 193, 662-672.

Cassidy, R.N., Roberts, M.E., and Colby, S.M. (2015). Validation of a Respiratory Symptom Questionnaire in Adolescent Smokers. Tob. Regul. Sci. 1, 121-128.

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. Intl. Immunopharmacol. 17, 625-632.

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

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(1), 28-36.

Deshmukh, H.S., Shaver, C., Case, L.M., Dietsch, M., Wesselkamper, S.C., Hardie, W.D., Korfhagen, T.R., Corradi, M., Nadel, J.A., and Borchers, M.T. (2008). Acrolein-activated matrix metalloproteinase 9 contributes to persistent mucin production. Am. J. Resp. Cell Mol. Biol. 38, 446-454.

Dijkstra, A.E., de Jong, K., Boezen, H.M., Kromhout, H., Vermeulen, R., Groen, H.J.M., et al. (2014). Risk factors for chronic mucus hypersecretion in individuals with and without COPD: influence of smoking and job exposure on CMH. Occup. Environ. Med. 71, 346-352.

Evans, C. M., Kim, K., Tuvim, M. J., & Dickey, B. F. (2009). Mucus hypersecretion in asthma: causes and effects. Curr. Opin. Pulm. Med. 15, 4–11.

Hardin, M., and Rennard, S.I. (2017). What's New with the St George's Respiratory Questionnaire and Why Do We Care? Chronic Obstr. Pulm. Dis. 4, 83-86.

Harmsen, Thomsen, S.F., Ingebrigtsen, T., Steffensen, I.E., Skadhauge, L.R., Kyvik, K.O., et al. (2010). Chronic mucus hypersecretion: prevalence and risk factors in younger individuals. Int. J. Tuberc. Lung Dis. 14, 1052-1058.

Hooper, L.G., Young, M.T., Keller, J.P., Szpiro, A.A., O'Brien, K.M., Sandler, D.P., et al. (2018). Ambient Air Pollution and Chronic Bronchitis in a Cohort of U.S. Women. Environ. Health Persp. 126, 027005-027005.

Kim, V., Han, M.K., Vance, G.B., Make, B.J., Newell, J.D., Hokanson, J.E., et al. (2011). The chronic bronchitic phenotype of COPD: an analysis of the COPDGene Study. Chest 140, 626-633. 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(2), 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.

Martinez, C.H., Kim, V., Chen, Y., Kazerooni, E.A., Murray, S., Criner, G.J., et al. (2014). The clinical impact of non-obstructive chronic bronchitis in current and former smokers. Respir. Med. 108, 491-499.

Regalado, J., Pérez-Padilla, R., Sansores, R., Páramo Ramirez, J.I., Brauer, M., Paré, P., et al. (2006). The effect of biomass burning on respiratory symptoms and lung function in rural Mexican women. Am. J. Resp. Crit. Care Med. 174, 901-905.

Shim, J.J., Dabbagh, K., Ueki, I.F., Dao-Pick, T., Burgel, P.R., Takeyama, K., Tam, D.C.W., and Nadel, J.A. (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., & Adler, K. B. (2004). A MARCKS-related peptide blocks mucus hypersecretion in a mouse model of asthma. Nat. Med. 10, 193.

Song, L., Tang, H., Liu, D., Song, J., Wu, Y., Qu, S., and Li, Y. (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.

Stott-Miller, M., Müllerová, H., Miller, B., Tabberer, M., El Baou, C., Keeley, T., et al. (2020). Defining Chronic Mucus Hypersecretion Using the CAT in the SPIROMICS Cohort. Int. J. Chron. Obstruct. Pulmon. Dis. 15, 2467.

Sunyer, J., Jarvis, D., Gotschi, T., Garcia-Esteban, R., Jacquemin, B., Aguilera, I., et al. (2006). Chronic bronchitis and urban air pollution in an international study. Occup. Environ. Med. 63, 836-843.

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

Vlahos, R., and Bozinovski, S. (2015). Preclinical murine models of chronic obstructive pulmonary disease. Eur. J. Pharmacol. 759, 265-271.

Wang, H., Yang, T., Wang, T., Hao, N., Shen, Y., Wu, Y., et al. (2018). Phloretin attenuates mucus hypersecretion and airway inflammation induced by cigarette smoke. Intl. Immunopharmacol. 55, 112-119.

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

Zemp, E., Elsasser, S., Schindler, C., Kunzli, N., Perruchoud, A.P., Domenighetti, G., et al. (1999). Long-term ambient air pollution and respiratory symptoms in adults (SAPALDIA study). Am. J. Resp. Crit. Care Med. 159, 1257-1266.