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Relationship: 2443


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

MCC, Decreased 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
Oxidative stress Leading to Decreased Lung Function adjacent Moderate Moderate Brendan Ferreri-Hanberry (send email) Open for comment. Do not cite
Oxidative stress Leading to Decreased Lung Function via CFTR dysfunction adjacent Moderate Moderate Arthur Author (send email) Open for comment. Do not cite
Oxidative Stress Leading to Decreased Lung Function via Decreased FOXJ1 adjacent Agnes Aggy (send email) Open for comment. Do not cite

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 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
All life stages 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

It is very well known that patients suffering from motile ciliopathies, such as primary ciliary dyskinesia, have impaired or absent MCC and lower lung function (reduced FEV1 and FVC) compared to their healthy counterparts (Halbeisen et al., 2018; Marthin et al., 2010; Wallmeier et al., 2020). In cystic fibrosis patients, decreased MCC (due to reduced airway hydration and changes in mucus chemical and viscoelastic properties) causes mucus build-up leading to mucus plugging in the airways and consequently to decreased lung function over time (Kerem et al., 2014; Mossberg et al., 1978; Regnis et al., 1994; Robinson and Bye, 2002; Szczesniak et al., 2017; Wanner et al., 1996). Mucus plugging due to decreased MCC is also considered a major cause of airway obstruction and airflow limitation in COPD patients (Dunican et al., 2021; Okajima et al., 2020) and asthmatics (Kuyper et al., 2003; Maxwell, 1985).

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

Changes in MCC rate are typically paralleled by effects on lung function in several studies where both endpoints have been assessed. In patients with primary ciliary dyskinesia, absence of cilia motion prevents normal MCC and consequently, lung function is reduced (Denizoglu Kulli et al., 2020). In cystic fibrosis patients, the ASL is depleted resulting in impaired MCC (Boucher, 2004). Although the known CFTR genotypes can result in a variety of phenotypes (Derichs, 2013), clinical data indicate that some specific gene defects, such as the p.Phe508del variant, are more frequently associated with decreased lung function indices (e.g. FEV1 % predicted, FVC % predicted, FEF25-75) (Kerem et al., 1990; Johansen et al., 1991; Schaedel et al., 2002). Both cigarette smoking and occupational exposure to biomass fumes led to slower MCC and reduced FEV1 % predicted and FEV1/FVC (Ferreira et al., 2018). Nasomucociliary clearance was slower in COPD smokers compared to former smokers with COPD or to nonsmokers (Ito et al., 2015). Allergen challenge in asthma patients resulted in both reduced MCC and FEV1, which could be reversed by inhalation of hypertonic saline solution (Alexis et al., 2017). In cystic fibrosis patients, treatment with mucolytic agents (Laube et al., 1996; McCoy et al., 1996; Quan et al., 2001; Elkins et al., 2006; Amin et al., 2011; Donaldson et al., 2018) or a CFTR potentiator (Rowe et al., 2014) improved both MCC and lung function (FEV1, FVC and FEF25-75).

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

Lung function is known to decrease with age, and several studies showed that mucus transport rates also decrease in older compared to younger individuals (Goodman et al., 1978; Uzeloto et al., 2021). Impaired MCC is also seen in chronic smokers, even prior to a clinically significant drop in lung function and the detection of small airway disease (Clunes et al., 2012a; Goodman et al., 1978; Lourenço et al., 1971; Uzeloto et al., 2021; Vastag et al., 1986), and in patients with obstructive lung disease and hence, poor lung function (Cruz et al., 1974; Vastag et al., 1986). Adult asthmatics also displayed decreased mucus transport rates/velocities in addition to decreased lung function (Ahmed et al., 1981; Bateman et al., 1983; Foster et al., 1982; Mezey et al., 1978). In patients with primary ciliary dyskinesia, absence of cilia motion prevents normal MCC and consequently, lung function is reduced (Denizoglu Kulli et al., 2020). In cystic fibrosis patients, the ASL is depleted resulting in impaired MCC (Boucher, 2004a). Although the known CFTR genotypes can result in a variety of phenotypes (Derichs, 2013), clinical data indicate that some specific gene defects, such as the p.Phe508del variant, are more frequently associated with decreased lung function indices (e.g. FEV1 % predicted, FVC % predicted, FEF25-75) (Johansen et al., 1991; Kerem et al., 1990; Schaedel et al., 2002). Unsurprisingly, results from studies with pharmacological agents aimed at restoring CFTR function do not only indicate enhanced MCC but also support improvements in lung function (Bennett et al., 2018; Donaldson et al., 2018; Rowe S. M. et al., 2014a). While the available data link these two KEs, causal evidence is not always available, and some inference is present. Therefore, we judge the biological plausibility of this KER as moderate.

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

Genetic defects leading to motile ciliopathies or defects in CFTR function are linked to impaired MCC. However, because of the genetic variety, not every defect, for example in the CFTR gene, also expresses an overt pulmonary phenotype. Other factors, such as low-level chronic inflammation may drive lung pathology by pathways independent of MCC. This might also explain the absence of differences in MCC between healthy smokers and smokers with COPD (Fleming et al., 2019). Not all studies looking to elucidate the effect of mucolytics on MCC report an improvement of lung function, even though mucus transport rates or tracheobronchial clearance significantly improve. These studies include, for example, some on the effects of hypertonic saline solution, NAC, ambroxol and 2-mercapto-ethane sulphonate (Clarke et al., 1979; Ericsson et al., 1987; Millar et al., 1985; Robinson et al., 1997; Würtemberger et al., 1988). This could be, at least in part, related to the fact that a sudden drop in lung function served as an indicator of patient distress in these studies, and interventions were halted when they occurred to ensure patient safety (Robinson et al., 1996). Another reason could be related to the mechanisms underlying mucus solubilization that may be completely independent of lung function. MCC is only one means by which mucus can be cleared from the lungs. Another one is cough clearance, and it is highly dependent on the properties of the ASL, in particular the ASL height (Knowles and Boucher, 2002).

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

Invariably, if mucus viscosity increases (independent of whether that results from increased mucus production (hypersecretion), depletion of the ASL or another cause) and MCC decreases, another mechanism comes into action to clear excess mucus: cough clearance. Cough constitutes a “backup” host defense by which acutely or chronically accumulated mucus is expelled through forceful, high-velocity airflow (Button et al., 2018; King, 2006). Our current understanding of the mechanical principles and biology of cough suggest that failure of cough clearance may also be a contributor to decreased lung function.

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

Sixteen Brazilian sugarcane workers aged 25±4 years, with a BMI of 24±3 kg/m2, with exhaled CO of 2.1±1.5 ppm, were examined during the non-harvest season and during the sugarcane burning harvest season. There was a non-significant decrease in saccharin transit time (from 8±1 min to 3±1 min) and a significant decrease  FEV1/FVC ratio (from 88.62±5.68 to 84.90±6.47) and %FEV1 (from 92.19±13.24 to 90.44±12.76) during harvest compared with the non-harvest season (Ferreira et al., 2018).

12 (6M/6F) mild allergic, non-smoking asthmatics ages 20–39 with skin sensitivity to house dust mites (HDM) and normal baseline lung function (FEV1 %pred > 80, FEV1/FVC ratio >0.70) inhaled sequential doses of inhaled HDM extract (D. farinae, Greer®, Lenoir, NC) delivered as 5 inhalations from a Devilbiss 646 nebulizer (mass median aerodynamic diameter of 5 um, GSD = 2.0). Five of the 12 patients responded to the allergen challenge with >10% reductions in FEV1 % predicted and reduction in whole lung MCC as evidenced by increased retention rates (mean Central TB Ave120Ret increased from 0.69 to 0.79 for baseline vs. allergen challenge respectively). This reduction in MCC significantly correlated with the post challenge 24 hour FEV1 (Bennett et al., 2011).

Treatment of patients with chronic bronchitis with bromhexine (3 x 16 mg/day) for 14 days resulted in mean changes in FEV1, FVC and FEV1/FVC of + 0.047 L + 0.033 L and +0.6%, respectively, with MCC at 6 h being 6.8% greater after treatment compared to baseline (Thomson et al., 1974). Treatment of patients with chronic bronchitis with ambroxol alone (2 x 30 mg/day) or with theophyllin (2 x 400 mg/day) and ambroxol (2 x 30 mg/day) for 7 days MCC/h improved from 18.3 ± 11.1% to 23.3 ± 13% and 29.6 ± 15.7%, respectively whereas lung function remained nearly unchanged with FEV1 predicted of 86.0 ± 9.78 at baseline vs 83.7 ± 9.27 (ambroxol only) and 83.1 ± 11.07 (combination) (Würtemberger et al., 1988).

Treatment of chronic bronchitics with N-acetylcysteine (4 mg/day by metered dose inhaler) for 16 weeks significantly improved sputum viscosity (-0.53 vs -0.67; differences between medians to placebo: 0-14 (-0.77 0.64)) and minimally improved FVC (3.0±0.21 vs 2.9± 0.18 L/s) and PEF (356.7 ±29.64 L/min vs 354.6±25.07) but not FEV1 (1.9±0.18 vs 2.0± 0.13 L/s) (Dueholm et al., 1992).

Treatment of asthmatics with salmeterol improved tracheobronchial clearance rates (AUC: 333±24%h vs 347±30%h in placebo) as well as FEV1 (76 ± 8), FVC (100 ± 5) and PEF % predicted (100 ± 7) compared to placebo (73 ± 8; 95 ± 5; 94 ± 7) (Hasani et al., 2003).

Treatment of mild-to-moderate bronchitics with 42 µg salmeterol slightly enhanced whole lung clearance in 2 hr (not significant; C10–2= 25±11% vs 22±10% in placebo), significantly increased mean  peripheral lung clearance (C10–2= 22±9% vs 17±10% in placebo) and significantly increased FEV1 %pred and FEF25–75 at 2 h compared to baseline (93±18%predicted, 2.45 ± 1.08 L/s vs 88±19%predicted, 2.27 ± 0.98 L/s in placebo) (Bennett et al., 2006).

Sputum induction by inhalation of hypertonic saline solution (5%) in asthmatics at 6 hr following challenge with LPS significantly improved FEV % predicted by approx. 20% and was accompanied by a ca. 6-fold increase in whole lung clearance (from 0.1 %/min to 0.6%/min) (Alexis et al., 2017).

133 cystic fibrosis patients (age (mean [SD]) was 21.1 (11.4) years and 46.4% were female. All participants had one copy of the G551D mutation, and 72.2% were compound heterozygous with F508del on the other allele.) completed a 6-month course of ivacaftor. Lung function improved from baseline FEV1% predicted of 82.6 (25.6) to 90.1 (25.0) (mean change, 6.7; 95% CI, 4.9–8.5). In a subgroup of 22 patients, particle clearance from the whole right lung was markedly increased. Average clearance through 60 minutes at 1 month post-treatment was more than twice the baseline value, reflecting substantially improved MCC (Rowe et al., 2014b). Inhalation of hypertonic saline solution (7%, 4 mL twice daily for 48 weeks) by cystic fibrosis patients improved FVC (by 82 mL; 95 percent confidence interval, 12 to 153) and FEV1 (by 68 mL; 95 percent confidence interval, 3 to 132) values, but not FEF25–75 (Elkins et al., 2006).

In cystic fibrosis patients that inhaled hypertonic saline solution without amiloride twice a day over a period of 14 days one-hour mucus clearance rates improved from baseline (9.3±1.6%) to 14.0±2.0% and increased FEV1 by 6.2%. FVC and FEF25-75 also improved by 1.8% and 13.1%, respectively (Donaldson et al., 2006).

Dornase alfa (recombinant human DNase) is currently used as a mucolytic to treat pulmonary disease in cystic fibrosis. It reduces mucus viscosity in the lungs, promoting improved clearance of secretions (Yang and Montgomery, 2021). In children with cystic fibrosis (mean: 8.4 yrs of age with FEV1 ≥95% predicted) treated with dornase alfa for 96 weeks, FEV1 % predicted improved by 3.2 ± 1.2, FVC % predicted improved by 0.7 ± 1.0, and FEF25-75 % predicted improved by 7.9 ± 2.3 compared to placebo (Quan et al., 2001). In young patients with cystic fibrosis (6-18 yrs of age with FEV1 ≥80% predicted) treated with dornase alfa for 96 weeks, FEF25-75 % predicted improved by 6.1±10.34 compared to placebo (Amin et al., 2011). In 10 adult cystic fibrosis patients receiving 2.5 mg rhDNase twice a day for 6 days, FEV1 and FVC increased by an average of 9.4 ± 3.5% and 12.7 ± 2.6%, respectively, as compared with a decrease of 1.8 ± 1.7% and an increase of 0.4±1.1% in the placebo group, respectively, although there were no significant changes in MCC (Laube et al., 1996). In 320 cystic fibrosis patients (7 to 57 yrs of age), dornase alfa treatment at 2.5 mg/day for 12 weeks (McCoy et al., 1996).

Saccharin transit times (a marker of nasal MCC) were higher in healthy current smokers and COPD smokers than in healthy controls (10.87 [7.29–17] min and 16.47 [8.25–20.15] min, respectively, vs 8.52 [5.54–13.91] min). These groups also differed in their lung function indices: FEV1 % predicted was 101.4 ± 12.37 in healthy controls, 96.41 ± 12.3 in healthy current smokers, and 67.96 ± 24.02 in COPD smokers. FVC % predicted was 103.1 ± 13.45 in healthy controls, 97.51 ± 12.88 in healthy current smokers, and 90.33 ± 29.27 in COPD smokers. FEV1/FVC % predicted was 82.15 [78.5–85] in healthy controls, 82.20 [79.2–84.1] in healthy current smokers, and 61.1 [55.3–67.2] in COPD smokers (Uzeloto et al., 2021). Saccharin transit time of smokers with COPD (16.5 [11–28] min, median [interquartile range 25–75%]) was slightly longer than that of current smokers (15.9 [10 –27] min), and both were longer compared with exsmokers with COPD (10.2 [6 –12] min) and nonsmokers (8 [6 –16] min). Lung function parameters for the groups were as follows: nonsmokers, FEV1/FVC 0.84 ± 0.09, FEV1 % predicted  103.2 ± 11.5, FVC % predicted 102.2 ± 13.3; current smokers, FEV1/FVC 0.76 ± 0.05, FEV1 % predicted  90.7 ± 7.4, FVC % predicted 96.3 ± 13.9; former smokers with COPD, FEV1/FVC 0.49 ± 0.08, FEV1 % predicted  46.8 ± 12.6, FVC % predicted 76.8 ± 18.5; current smokers with COPD, FEV1/FVC 0.66 ± 0.16, FEV1 % predicted  48.7 ± 16.8, FVC % predicted 71.7 ± 13.0 (Ito et al., 2015).  

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

Six asymptomatic patients with bronchial asthma and a history of allergic pollenosis and episodic bronchospasm consistent with ragweed hypersensitivity wer challenged by inhalation of an aqueous, short ragweed antigen extract (Greer Laboratories, Lenoir, N.C.), diluted with a phosphate-buffered saline solution. Mean tracheal mucus velocity (TMV) decreased to 72% of baseline immediately after challenge when specific airway conductance (SGaw), and FEV1 showed a maximal decrease, with a further decrease to 47% of baseline after 1 h, when SGaw and FEV1 had returned to baseline values (Mezey et al., 1978).

Treatment of chronic bronchitics with N-acetylcysteine (3 x 200 mg/day) for 4 weeks significantly decreased sputum thickness, increased sputum pourability from 650% glycerol time (at baseline) to 320% glycerol time on day 21 and PEFR on days 28 (+5%), 35 (+6%) and 42 (+7%) and FEV1 on days 21 (+2%), 28(+3%), 35 (+4%) and 42 (+5%) compared to baseline (ca. 33% predicted and 28% predicted, respectively) (Aylward et al., 1980).

Treatment of mild-to-moderate bronchitics with 42 µg salmeterol slightly enhanced whole lung clearance in 2 hr (not significant; C10–2= 25±11% vs 22±10% in placebo), significantly increased mean  peripheral lung clearance (C10–2= 22±9% vs 17±10% in placebo) and significantly increased FEV1 %pred and FEF25–75 at 2 h compared to baseline (93±18%predicted, 2.45 ± 1.08 L/s vs 88±19%predicted, 2.27 ± 0.98 L/s in placebo) , and significantly increased FEV1 %pred and FEF25–75 at both 1 (92±19%predicted, 2.44 ± 1.14 L/s) and 2 h (93±18%predicted, 2.45 ± 1.08 L/s) compared to baseline (pre-dose; 90 ± 20%predicted, 2.16 ± 0.92 L/s) (Bennett et al., 2006).

In cystic fibrosis patients on a 6-month ivacaftor regimen, FEV1% improvement was detectable as soon as the 1-month follow-up visit (mean change, 6.7; 95% CI, 5.2–8.3) (Rowe et al., 2014b). MCC remained at elevated level at the month 3 visit (Donaldson et al., 2018).

One-hour mucus-clearance rates in cystic fibrosis patients receiving hypertonic saline with placebo were significantly faster than in the group receiving hypertonic saline with amiloride (14.0±2.0 vs. 7.0±1.5 %), and the durability of response following the inhalation of hypertonic saline with placebo was ≥8 hours (Donaldson et al., 2006).  

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

The evidences for this KER come from and therefore apply to humans.


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

Ahmed, T., Greenblatt, D.W., Birch, S., Marchette, B., and Wanner, A. (1981). Abnormal mucociliary transport in allergic patients with antigen-induced bronchospasm: role of slow reacting substance of anaphylaxis. Am. Rev. Respir. Dis. 124, 110-114.

Alexis, N.E., Bennett, W., and Peden, D.B. (2017). Safety and benefits of inhaled hypertonic saline following airway challenges with endotoxin and allergen in asthmatics. J. Asthma 54, 957-960.

Amin, R., Subbarao, P., Lou, W., Jabar, A., Balkovec, S., Jensen, R., et al. (2011). The effect of dornase alfa on ventilation inhomogeneity in patients with cystic fibrosis. Eur. Respir. J. 37, 806-812.

Aylward, M., Maddock, J., and Dewland, P. (1980). Clinical evaluation of acetylcysteine in the treatment of patients with chronic obstructive bronchitis: a balanced double-blind trial with placebo control. Eur. J. Respir. Dis. Suppl. 111, 81-89.

Bateman, J., Pavia, D., Sheahan, N., Agnew, J., and Clarke, S. (1983). Impaired tracheobronchial clearance in patients with mild stable asthma. Thorax 38, 463-467.

Bennett, W.D., Zeman, K.L., Laube, B.L., Wu, J., Sharpless, G., Mogayzel, P.J., Jr., et al. (2018). Homogeneity of Aerosol Deposition and Mucociliary Clearance are Improved Following Ivacaftor Treatment in Cystic Fibrosis. J. Aerosol Med. Pulm. Drug Delivery 31, 204-211. 

Bennett, W.D., Almond, M.A., Zeman, K.L., Johnson, J.G., and Donohue, J.F. (2006). Effect of salmeterol on mucociliary and cough clearance in chronic bronchitis. Pulmon. Pharmacol. Therap. 19, 96-100.

Bennett, W.D., Herbst, M., Alexis, N.E., Zeman, K.L., Wu, J., Hernandez, M.L., et al. (2011). Effect of inhaled dust mite allergen on regional particle deposition and mucociliary clearance in allergic asthmatics. Clin. Exp. Allergy 41, 1719-1728. 

Boucher, R. (2004). New concepts of the pathogenesis of cystic fibrosis lung disease. Eur. Respir. J. 23, 146-158.

Button, B., Goodell, H.P., Atieh, E., Chen, Y.-C., Williams, R., Shenoy, S., et al. (2018). Roles of mucus adhesion and cohesion in cough clearance. Proc. Natl. Acad. Sci. U.S.A. 115, 12501-12506. 

Clunes, L.A., Davies, C.M., Coakley, R.D., Aleksandrov, A.A., Henderson, A.G., Zeman, K.L., et al. (2012). Cigarette smoke exposure induces CFTR internalization and insolubility, leading to airway surface liquid dehydration. FASEB J. 26, 533-545. 

Cruz, R.S., Landa, J., Hirsch, J., and Sackner, M.A. (1974). Tracheal mucous velocity in normal man and patients with obstructive lung disease; effects of terbutaline. Am. Rev. Respir. Dis. 109, 458-463.

Denizoglu Kulli, H., Gurses, H.N., Zeren, M., Ucgun, H., and Cakir, E. (2020). Do pulmonary and extrapulmonary features differ among cystic fibrosis, primary ciliary dyskinesia, and healthy children? Pediatr. Pulmonol. 55, 3067-3073. 

Derichs, N. (2013). Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis. Eur. Respir. J. 22, 58-65.

Donaldson, S.H., Bennett, W.D., Zeman, K.L., Knowles, M.R., Tarran, R., and Boucher, R.C. (2006). Mucus Clearance and Lung Function in Cystic Fibrosis with Hypertonic Saline. N. Engl. J. Med. 354, 241-250. 

Donaldson, S.H., Laube, B.L., Corcoran, T.E., Bhambhvani, P., Zeman, K., Ceppe, A., et al. (2018). Effect of ivacaftor on mucociliary clearance and clinical outcomes in cystic fibrosis patients with G551D-CFTR. JCI Insight 3, e122695. 

Dueholm, M., Nielsen, C., Thorshauge, H., Evald, T., Hansen, N.-C., Madsen, H., et al. (1992). N-acetylcysteine by metered dose inhaler in thetreatment of chronic bronchitis: a multi-centre study. Respir. Med. 86, 89-92.

Dunican, E.M., Elicker, B.M., Henry, T., Gierada, D.S., Schiebler, M.L., Anderson, W., et al. (2021). Mucus plugs and emphysema in the pathophysiology of airflow obstruction and hypoxemia in smokers. Am. J. Respir. Crit. Care Med. 203, 957-968.

Elkins, M.R., Robinson, M., Rose, B.R., Harbour, C., Moriarty, C.P., Marks, G.B., et al. (2006). A Controlled Trial of Long-Term Inhaled Hypertonic Saline in Patients with Cystic Fibrosis. N. Engl. J. Med. 354, 229-240. 

Ferreira, A.D., Ramos, E.M.C., Trevisan, I.B., Leite, M.R., Proença, M., de Carvalho-Junior, L.C.S., et al. (2018). Função pulmonar e depuração mucociliar nasal de cortadores de cana-de-açúcar brasileiros expostos à queima de biomassa. Rev. Bras. Saúde Ocup. 43,e6.

Foster, W., Langenback, E., and Bergofsky, E. (1982). "Lung mucociliary function in man: interdependence of bronchial and tracheal mucus transport velocities with lung clearance in bronchial asthma and healthy subjects," in Inhaled Particles V. Elsevier), 227-244.

Goodman, R., Yergin, B., Landa, J., Golinvaux, M., and Sackner, M. (1978). Relationship of smoking history and pulmonary function tests to tracheal mucous velocity in nonsmokers, young smokers, ex-smokers, and patients with chronic bronchitis. Am. Rev. Respir. Dis. 117, 205-214.

Halbeisen, F.S., Goutaki, M., Spycher, B.D., Amirav, I., Behan, L., Boon, M., et al. (2018). Lung function in patients with primary ciliary dyskinesia: an iPCD Cohort study. Eur. Respir. J. 52, 1801040.

Hasani, A., Toms, N., O'Connor, J., Dilworth, J., and Agnew, J. (2003). Effect of salmeterol xinafoate on lung mucociliary clearance in patients with asthma. Respir. Med. 97, 667-671.

Ito, J.T., Ramos, D., Lima, F.F., Rodrigues, F.M., Gomes, P.R., Moreira, G.L., et al. (2015). Nasal Mucociliary Clearance in Subjects With COPD After Smoking Cessation. Respir. Care 60, 399-405. 

Johansen, H.K., Nir, M., Koch, C., Schwartz, M., and Høiby, N. (1991). Severity of cystic fibrosis in patients homozygous and heterozygous for ΔF508 mutation. Lancet 337, 631-634.

Kerem, E., Corey, M., Kerem, B.-s., Rommens, J., Markiewicz, D., Levison, H., et al. (1990). The relation between genotype and phenotype in cystic fibrosis—analysis of the most common mutation (ΔF508). N. Engl. J. Med. 323, 1517-1522.

Kerem, E., Viviani, L., Zolin, A., MacNeill, S., Hatziagorou, E., Ellemunter, H., et al. (2014). Factors associated with FEV1 decline in cystic fibrosis: analysis of the ECFS Patient Registry. Eur. Respir. J. 43, 125-133. 

Kesimer, M., Smith, B.M., Ceppe, A., Ford, A.A., Anderson, W.H., Barr, R.G., et al. (2018). Mucin concentrations and peripheral airway obstruction in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 198, 1453-1456.

King, M. (2006). Physiology of mucus clearance. Paediatr. Respir. Rev. 7 Suppl 1, S212-214. 

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