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Relationship: 2859

Title

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 Decreased lung function

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Increase, Mucin production

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Decreased lung function

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	Moderate	Moderate	Cataia Ives (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 Do not cite	Under Development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
Homo sapiens	Homo sapiens	Moderate	NCBI
Rattus norvegicus	Rattus norvegicus	Moderate	NCBI
Mustela furo	Mustela putorius furo	Moderate	NCBI

Sex Applicability

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

Sex	Evidence
Unspecific

Life Stage Applicability

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

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 (Ramos, Krahnke, and Kim 2014; Rose and Voynow 2006). However, under chronic exposure conditions, with a support of increased number of specialized mucin-expressing goblet cells, mucus production sustains. When intracellular mucin is secreted into the lumen, it gets hydrated and expands massively (Verdugo 1991) leading to airway narrowing which ultimately decreases the airflow to lungs. This process may lead to airway obstruction and progressive decline in lung function (Aoshiba and Nagai 2004; Victor Kim and Criner 2015; Vestbo, Prescott, and Lange 1996). The association between increased mucin production and lung function decrease is correlative and is described in human patients as well as in animal models. The link between mucus hypersecretion and decreased lung function as well as increased hospitalization / mortality rates is shown in various clinical studies (Ekberg-Aronsson et al. 2005; Vestbo and Rasmussen 1989; Lahousse et al. 2017; Corhay et al. 2013). Lung function is commonly tested through spirometry by measuring forced expiratory volume in 1 s (FEV1) – the maximum volume of air that can forcibly be exhaled during the first second following maximal inhalation and forced vital capacity (FVC) – the maximum volume of air that can forcibly be exhaled following maximal inhalation.

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

The relevant research articles supporting this KER were identified using keywords: “mucin” or “mucus” AND terms for pulmonary function test (spirometry) parameters such as “FEV/forced expiratory volume” or “FVC/forced vital capacity” or “VC/ vital capacity” or “PEF/peak expiratory flow” as well as other search terms of lung capacity measures such as “plethysmography”. Referenced articles within retrieved studies and reviews were also consulted. Not all retrieved articles were included as a support for this KER since they generally repeat the same conclusions listed in the evidence texts below.

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 FEV in 1 s (% predicted) and with FEV1/FVC ratio (Caramori et al., 2009; Innes et al., 2006), model animal studies support the link between increased production of mucins and decrease in lung function (Feng et al. 2019; He et al. 2017; Raju et al. 2016), and epidemiological evidence indicates an association between mucus hypersecretion and decreased lung function (Allinson et al., 2015; Pistelli et al., 2003; Vestbo et al., 1996). The cause-effect relationship between increased mucin production and decreased lung function cannot be conclusively proven, but the link between mucus hypersecretion and airway obstruction / lung function decline is clinically accepted. However, increased mucin production needs to be persistent in order to result in sustained mucus hypersecretion. In addition, impaired mucociliary clearance contributes to airway obstruction (Whitsett 2018) and it is currently unclear whether chronic mucus hypersecretion alone is sufficient to elicit a decrease in lung function. Considering all above-mentioned, we suggest moderate biological plausibility for this KER.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

The evidences compiled below show association between increased mucin production (upstream KE) and decreased lung function (downstream KE). We present several studies on this association that represent the general consensus in the scientific and medical field, more information on the correlation between mucin/mucus concentration and lung function decrease parameters can be derived also from number of review articles (Button, Anderson, and Boucher 2016; Pistelli, Lange, and Miller 2003; Ramos, Krahnke, and Kim 2014; Shen et al. 2018).

The volume of epithelial mucin stores, assessed as volume of mucin per surface area of basal lamina, was larger in bronchial biopsies from smokers with airflow obstruction than in those without and correlated with the FEV1 (Forced expiratory volume in 1 s) /FVC (Forced vital capacity) ratio. The increase in stored mucin occurs because of an increase in MUC5AC levels and despite a decrease in MUC5B (Innes et al. 2006).
MUC5AC protein and mucus glycoconjugate levels were increased in the airways of COPD patients compared with non-COPD patients. Lung function tests of COPD patients suggested function deterioration compared with non-COPD group (Ma et al. 2005).
MUC5AC expression in bronchial epithelium was inversely correlated with FEV1 (% predicted) in COPD patients (Caramori et al. 2009).

Increased MUC5AC concentrations in sputum were reliably associated with parameters of lung function decline, including decreased FEV1, FEF25-75% (forced expiratory flow, midexpiratory phase), RV/TLC (residual volume/total lung capacity ratio) (Radicioni et al. 2021).
The MUC5AC levels in the bronchoalveolar lavage fluid of patients with interstitial lung disease were negatively correlated with FEV1/FVC (r=-0.761, p=0.000), FEV1 predicted value (r=-0.668, p=0.002), and diffusing capacity (r=-0.606, p=0.006) (Wei et al. 2019).
In bronchial tissues of COPD patients MUC5AC mRNA levels were negatively correlated with FEV1/FVC (P = 0.01), FEV1% predicted (P = 0.01), V(50)% predicted and V(25)% predicted data (markers of small airway obstruction) (r = -0.53, r = -0.53, r = -0.48, r = -0.43, P < 0.01) (Wang et al. 2007). 
Cigarette smoke (CS)-exposed ferrets displayed greater MUC5AC and MUC5B staining in the airway epithelium. PAS-positive goblet cell area was also higher in CS-exposed ferret airways. Inspiratory capacity, a sensitive marker of airway obstruction, was significantly reduced in CS-exposed ferrets (Raju et al. 2016).
Rats exposed to biomass fuel (BMF) and motor vehicle exhaust (MVE) had increased levels of MUC5AC immunostaining and AB/PAS staining in the lung sections compared to the controls at 3 months. After 7 months of exposure to BMF or MVE significant reductions in lung function were observed, manifested by increased resistance and functional residual capacity (FRC), and decreased dynamic pulmonary compliance (Cdyn), peak expiratory flow (PEF) and FEV at 20 ms/FVC (He et al. 2017).

In allergen challenged rats statistically significant changes is lung function parameters were observed by 1 to 3 days of challenge (reductions in inspiratory capacity, functional residual capacity, FVC, PEF, maximum mid-expiratory flow and increases in respiratory system resistance and lung elastance). Mucin content (measured by electrophoretic mobility shift assay) in the bronchoalveolar lavage fluid samples was increased from day 1, and up to 6 days after antigen challenge and correlated with the increases in PAS-positive cells in the bronchial epithelium (Celly et al. 2006).

The following evidences support the notion of causality between upstream KE and downstream KE.

The authors used a peptide derived from the myristoylated alanine-rich C kinase substrate protein NH2-terminal sequence (MANS) which was shown to selectively block methacholine (MCh)-induced mucin hypersecretion in mouse model of asthma (Singer et al. 2004). MCh-induced mucin secretion was significantly inhibited in MANS-pretreated mouse airways. MCh-induced fall in specific airway conductance (sGaw) was partially inhibited by MANS peptide (Agrawal et al. 2007).
In acute exacerbation of chronic obstructive pulmonary disease (AECOPD) rat model MUC5AC mRNA and protein levels as well as mucous glycoconjugates (AB/PAS staining) were elevated, and increased phosphorylations of EGFR, PI3K and AKT were observed. Concomitantly, lung function parameters were decreased. Administration of Louqin Zhisou decoction (LQZS; Chinese herbal formula) to AECOPD rats attenuated the levels of phosphorylated EGFR, PI3K and AKT, decreased elevated MUC5AC levels and AB/PAS staining, and resulted in improved maximal voluntary ventilation (Feng et al. 2019). Similarly, in the study by Lin and colleagues, EGFR, p38MAPK and MUC5AC levels were increased along with decreases in lung function parameters (FVC, FEV0.1, FEV0.3, FEV0.1/FVC and FEV0.3/FVC) in COPD model rats whereas electroacupuncture at "Zusanli" (ST36) reversed both the increased levels of EGFR, p38MAPK and MUC5AC and the decreased levels of the lung function parameters (Lin et al. 2021). These data combined with the accepted knowledge in the field suggest causal relationship across the axis EGFR/increased mucin production/decreased lung function.

The following evidences show association between chronic mucus hypersecretion and decreased lung function. We include these evidences as supporting information based on assumption that increased mucin production is a prerequisite for chronic mucus hypersecretion.

Chronic mucus hypersecretion was significantly and consistently associated with decline in lung function, i.e. FEV1 and an increased risk of subsequent hospitalization from COPD (Vestbo, Prescott, and Lange 1996).
Chronic mucus hypersecretion was associated with both a lower FEV1 and faster FEV1 decline (Allinson et al. 2016).
Several other patient studies of COPD and chronic bronchitis show correlations between chronic mucus hypersecretion symptoms such as long-term (at least 3 months and usually up to 2 years and more) cough, sputum production, presence of phlegm on most days, with lower FEV1% and FVC% (de Oca et al. 2012; Lahousse et al. 2017; Corhay et al. 2013; V. Kim et al. 2016; Liang et al. 2017).

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

Physiological response to stressors that increase mucin production often is resolved after stressor exposure is eliminated, and the normal function of the airway is restored. For this KER to occur, sustained mucin production should ensue. Moreover, the KER is based on assumption that increased mucin production logically leads to mucin hypersecretion. However, when mucin secretion is inhibited (e.g. through MANS peptide (Singer et al. 2004)), increase in mucin production might not translate into mucin hypersecretion. A study of endobronchial biopsies from patients with mild and moderate asthma showed an increase in stored mucin compared with healthy controls. Stored mucin levels were similar in mild and moderate asthma patients, however secreted mucin was significantly lower in mild asthma patients than in moderate asthma patients (28.4 ± 6.3 versus 73.5 ± 47.5 µg/ml). These data add uncertainty to the KER by signifying the role of mucin secretion which is needed for downstream KE to occur (Ordoñez et al. 2001).

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

Modulating Factor (MF)	MF Specification	Effect(s) on the KER	Reference(s)
Mucociliary clearance (MCC)	Mucus removal through ciliary movement	Impaired MCC contributes to decreased lung function (see also AOPs 411, 424, 425)	Ramos, Krahnke, and Kim 2014

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

^{Below we list some quantitative aspects of the response relationship.}

Response-response Relationship

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

The evidences below are correlative and are not sufficient to conclude on causality of the KER.

COPD patients with decreased lung function had increased mucin expression. MUC5AC protein levels detected by immunohistochemistry were significantly higher (0.27%±0.09%) in COPD group compared with non-COPD group (0.20%±0.10%) Similarly, histopathological analysis of goblet cells with AB/PAS staining (detection of mucus glycoconjugates) revealed significantly higher amount of goblet cells (0.20%±0.10%) in COPD group than in the non-COPD group (0.13%±0.06%). Lung function tests operated on patients indicated significantly lower FEV1/FVC ratio and FEV1% in COPD group (FEV1/FVC: 63.78% ±6.60%, FEV1%: 77.56%±12.74%) compared to non-COPD group (FEV1/FVC: 79.80%±4.47%, FEV1%: 92.05%±15.17%). (Ma et al. 2005).
The area occupied by AB/PAS stained cells in the bronchial submucosal glands was significantly increased in COPD patients [20% (5.5–31.7%) gland area] in comparison to smokers with normal lung function [9.5% (2.5–17.5%)] and non-smokers [2% (0.4–6.2%)]. The area occupied by MUC5AC stained cells in the bronchial epithelium was also increased in smokers (with ⁄ without COPD) [73.5% (25–92%) epithelial area] compared with non-smokers [15% (2.7–32%)]. MUC5AC expression inversely correlated with FEV1 (% of predicted), indicating a potential role of MUC5AC in the pathogenesis of airflow obstruction in COPD (Caramori et al. 2009).
Following exposure to smoke from 3R4F research cigarettes for 1 h twice daily for 6 months, ferrets showed increased mucin production, increased number of goblet cells and chronic mucus hypersecretion (histology, PAS staining, MUC5AC and MUC5B 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).
Increased MUC5AC concentration in sputum was associated with lung function decrease parameters such as decreased FEV1, FEF25-75%, RV/TLC. Statistical modelling of 3-year longitudinal data indicated that baseline MUC5AC (but not MUC5B) concentration is a significant predictor for lung function decrease (FEV1 (p=0.010), FEV1/FVC (p=0.013), FEF25–75% (p=0.0005), FVC (p=0.14), CAT (COPD assessment test) score decline (p<0.0001)). Current smokers at-risk for COPD with raised baseline visit MUC5AC concentrations showed decline in lung function over 4 years whereas former smokers at-risk for COPD with normal baseline MUC5AC concentrations did not show lung function decline during the same observational period (Radicioni et al. 2021).
AECOPD rat model showed declines in lung function parameters such as forced expiratory volume in 0.3 second (FEV0.3), FEV0.3/FVC% and maximal voluntary ventilation MVV (P < 0.01) measured with pulmonary functionality test machine AniRes2005. AB/PAS-staining in rat airway epithelium was 18.73 ± 2.38% compared to 0.02 ± 0.02% in control animals. Similarly, MUC5AC mRNA and protein levels were increased in AECOPD rats. Administration of LQZS to AECOPD rats decreased AB/PAS staining to 1.49 ± 1.18%, abolished AECOPD-related MUC5AC mRNA and protein upregulation, and resulted in improved MVV parameter (Feng et al. 2019).

Time-scale

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

An observational longitudinal study showed that raised MUC5AC concentrations at initial monitoring visit of smokers at-risk for COPD resulted in significant lung function decline (FEV1) over 4 years (Radicioni et al. 2021).

In longitudinal follow-up studies of patients with chronic mucus hypersecretion an excess decline in FEV1 was recognized throughout years, suggesting that mucus hypersecretion may lead to progressive lung function decline in time (Sherman et al. 1992; Vestbo, Prescott, and Lange 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, corresponding to an additional decrement of 3.6 ± 2.5 ml/yr per occasion (Allinson et al. 2016).

Generally, it is observed that the prevalence of chronic mucus hypersecretion increases with age (Viegi et al. 2007) indicating that long-term exposures are needed for the stressor-induced increase in mucin production to develop into chronic mucus hypersecretion with an eventual risk of lung function decline.

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

Increased mucin production correlating with decreased lung function was shown in human patients and animal models (ferret and rodents).

References

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

Agrawal, A., S. Rengarajan, K. B. Adler, A. Ram, B. Ghosh, M. Fahim, and B. F. Dickey. 2007. "Inhibition of mucin secretion with MARCKS-related peptide improves airway obstruction in a mouse model of asthma." J Appl Physiol (1985) 102 (1): 399-405. https://doi.org/10.1152/japplphysiol.00630.2006.

Allinson, J. P., R. Hardy, G. C. Donaldson, S. O. Shaheen, D. Kuh, and J. A. Wedzicha. 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 (6): 662-72. https://doi.org/10.1164/rccm.201511-2210OC.

Aoshiba, Kazutetsu, and Atsushi Nagai. 2004. "Differences in airway remodeling between asthma and chronic obstructive pulmonary disease." Clinical Reviews in Allergy & Immunology 27 (1): 35-43. https://doi.org/10.1385/criai:27:1:035. http://dx.doi.org/10.1385/CRIAI:27:1:035.

Button, B., W. H. Anderson, and R. C. Boucher. 2016. "Mucus Hyperconcentration as a Unifying Aspect of the Chronic Bronchitic Phenotype." Ann Am Thorac Soc 13 Suppl 2 (Suppl 2): S156-62. https://doi.org/10.1513/AnnalsATS.201507-455KV.

Caramori, G., P. Casolari, C. Di Gregorio, M. Saetta, S. Baraldo, P. Boschetto, K. Ito, L. M. Fabbri, P. J. Barnes, I. M. Adcock, G. Cavallesco, K. F. Chung, and A. Papi. 2009. "MUC5AC expression is increased in bronchial submucosal glands of stable COPD patients." Histopathology 55 (3): 321-31. https://doi.org/10.1111/j.1365-2559.2009.03377.x.

Celly, C. S., A. House, S. J. Sehring, X. Y. Zhang, H. Jones, J. A. Hey, R. W. Egan, and R. W. Chapman. 2006. "Temporal profile of forced expiratory lung function in allergen-challenged Brown-Norway rats." Eur J Pharmacol 540 (1-3): 147-54. https://doi.org/10.1016/j.ejphar.2006.04.020.

Corhay, J. L., W. Vincken, M. Schlesser, P. Bossuyt, and J. Imschoot. 2013. "Chronic bronchitis in COPD patients is associated with increased risk of exacerbations: a cross-sectional multicentre study." Int J Clin Pract 67 (12): 1294-301. https://doi.org/10.1111/ijcp.12248.

de Oca, M. M., R. J. Halbert, M. V. Lopez, R. Perez-Padilla, C. Tálamo, D. Moreno, A. Muiño, J. R. Jardim, G. Valdivia, J. Pertuzé, and A. M. Menezes. 2012. "The chronic bronchitis phenotype in subjects with and without COPD: the PLATINO study." Eur Respir J 40 (1): 28-36. https://doi.org/10.1183/09031936.00141611.

Ekberg-Aronsson, M., K. Pehrsson, J. A. Nilsson, P. M. Nilsson, and C. G. Löfdahl. 2005. "Mortality in GOLD stages of COPD and its dependence on symptoms of chronic bronchitis." Respir Res 6 (1): 98. https://doi.org/10.1186/1465-9921-6-98.

Feng, F., J. Du, Y. Meng, F. Guo, and C. Feng. 2019. "Louqin Zhisou Decoction Inhibits Mucus Hypersecretion for Acute Exacerbation of Chronic Obstructive Pulmonary Disease Rats by Suppressing EGFR-PI3K-AKT Signaling Pathway and Restoring Th17/Treg Balance." Evid Based Complement Alternat Med 2019: 6471815. https://doi.org/10.1155/2019/6471815.

He, F., B. Liao, J. Pu, C. Li, M. Zheng, L. Huang, Y. Zhou, D. Zhao, B. Li, and P. Ran. 2017. "Exposure to Ambient Particulate Matter Induced COPD in a Rat Model and a Description of the Underlying Mechanism." Sci Rep 7: 45666. https://doi.org/10.1038/srep45666.

Innes, A. L., P. G. Woodruff, R. E. Ferrando, S. Donnelly, G. M. Dolganov, S. C. Lazarus, and J. V. Fahy. 2006. "Epithelial mucin stores are increased in the large airways of smokers with airflow obstruction." Chest 130 (4): 1102-8. https://doi.org/10.1378/chest.130.4.1102.

Kim, V., H. Zhao, A. M. Boriek, A. Anzueto, X. Soler, S. P. Bhatt, S. I. Rennard, R. Wise, A. Comellas, J. W. Ramsdell, G. L. Kinney, M. K. Han, C. H. Martinez, A. Yen, J. Black-Shinn, J. Porszasz, G. J. Criner, N. A. Hanania, A. Sharafkhaneh, J. D. Crapo, B. J. Make, E. K. Silverman, and J. L. Curtis. 2016. "Persistent and Newly Developed Chronic Bronchitis Are Associated with Worse Outcomes in Chronic Obstructive Pulmonary Disease." Ann Am Thorac Soc 13 (7): 1016-25. https://doi.org/10.1513/AnnalsATS.201512-800OC.

Kim, Victor, and Gerard J Criner. 2015. "The chronic bronchitis phenotype in chronic obstructive pulmonary disease: features and implications." Current Opinions in Pulmonary Medicine 21 (2): 133-141.

Lahousse, L., L. J. M. Seys, G. F. Joos, O. H. Franco, B. H. Stricker, and G. G. Brusselle. 2017. "Epidemiology and impact of chronic bronchitis in chronic obstructive pulmonary disease." Eur Respir J 50 (2). https://doi.org/10.1183/13993003.02470-2016.

Liang, Y., Y. Chen, R. Wu, M. Lu, W. Yao, J. Kang, B. Cai, X. Zhou, Z. Liu, P. Chen, D. Sun, J. Zheng, G. Wang, Y. Feng, and Y. Xu. 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 (12): 5120-5130. https://doi.org/10.21037/jtd.2017.11.54.

Lin, X. G., W. Li, S. Y. Xiang, S. B. Wu, X. F. Zhang, C. W. Jiang, Z. B. Liu, and Y. N. Chen. 2021. "[Electroacupuncture improves lung function by suppressing mucin-5AC mediated EGFR-p38MAPK signaling and inflammation reaction in chronic obstructive pulmonary disease rats]." Zhen Ci Yan Jiu 46 (3): 180-6. https://doi.org/10.13702/j.1000-0607.200420.

Ma, R., Y. Wang, G. Cheng, H. Z. Zhang, H. Y. Wan, and S. G. Huang. 2005. "MUC5AC expression up-regulation goblet cell hyperplasia in the airway of patients with chronic obstructive pulmonary disease." Chin Med Sci J 20 (3): 181-4.

Ordoñez, C. L., R. Khashayar, H. H. Wong, R. Ferrando, R. Wu, D. M. Hyde, J. A. Hotchkiss, Y. Zhang, A. Novikov, G. Dolganov, and J. V. Fahy. 2001. "Mild and moderate asthma is associated with airway goblet cell hyperplasia and abnormalities in mucin gene expression." Am J Respir Crit Care Med 163 (2): 517-23. https://doi.org/10.1164/ajrccm.163.2.2004039.

Pistelli, R., P. Lange, and D. L. Miller. 2003. "Determinants of prognosis of COPD in the elderly: mucus hypersecretion, infections, cardiovascular comorbidity." Eur Respir J Suppl 40: 10s-14s. https://doi.org/10.1183/09031936.03.00403403.

Radicioni, G., A. Ceppe, A. A. Ford, N. E. Alexis, R. G. Barr, E. R. Bleecker, S. A. Christenson, C. B. Cooper, M. K. Han, N. N. Hansel, A. T. Hastie, E. A. Hoffman, R. E. Kanner, F. J. Martinez, E. Ozkan, R. Paine, 3rd, P. G. Woodruff, W. K. O'Neal, R. C. Boucher, and M. Kesimer. 2021. "Airway mucin MUC5AC and MUC5B concentrations and the initiation and progression of chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort." Lancet Respir Med 9 (11): 1241-1254. https://doi.org/10.1016/s2213-2600(21)00079-5.

Raju, S. V., H. Kim, S. A. Byzek, L. P. Tang, J. E. Trombley, P. Jackson, L. Rasmussen, J. M. Wells, E. F. Libby, E. Dohm, L. Winter, S. L. Samuel, K. R. Zinn, J. E. Blalock, T. R. Schoeb, M. T. Dransfield, and S. M. Rowe. 2016. "A ferret model of COPD-related chronic bronchitis." JCI Insight 1 (15): e87536. https://doi.org/10.1172/jci.insight.87536.

Ramos, F. L., J. S. Krahnke, and V. Kim. 2014. "Clinical issues of mucus accumulation in COPD." Int J Chron Obstruct Pulmon Dis 9: 139-50. https://doi.org/10.2147/copd.S38938.

Rose, M. C., and J. A. Voynow. 2006. "Respiratory tract mucin genes and mucin glycoproteins in health and disease." Physiol Rev 86 (1): 245-78. https://doi.org/10.1152/physrev.00010.2005.

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