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Relationship: 2443
Title
MCC, Decreased leads to Decreased lung function
Upstream event
Downstream event
Key Event Relationship Overview
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 Do not cite | |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 Do not cite | |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 Do not cite |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
| Term | Scientific Term | Evidence | Link |
|---|---|---|---|
| Homo sapiens | Homo sapiens | High | NCBI |
Sex Applicability
| Sex | Evidence |
|---|---|
| Mixed | High |
Life Stage Applicability
| Term | Evidence |
|---|---|
| All life stages | High |
Key Event Relationship Description
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
Evidence Supporting this KER
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
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.
Empirical Evidence
Occupational exposure to biomass combustion products resulted in slower MCC and reduced FEV1 % predicted and FEV1/FVC (Ferreira et al., 2018).
Compared to healthy controls, current smokers without airway obstruction and current smokers with COPD exhibited longer saccharin transit times, indicative of impaired MCC, and lower FEV1 % predicted and FEV1/FVC (Uzeloto et al., 2021). Similarly, nasomucociliary clearance was slower in COPD smokers compared to former smokers with COPD or to nonsmokers (Ito et al., 2015). Additionally, mucus plug density—assessed by CT imaging—and mucoid (rather than watery) consistency were inversely related to FEF25–75% and associated with increased RV/TLV (Kesimer et al., 2018).
Asthma patients responded to allergen challenge with a reduction in both MCC and FEV1 (Bennett et al., 2011; Mezey et al., 1978), which could be rescued by inhalation with hypertonic saline solution (Alexis et al., 2017).
Multiple studies interrogating the effect of mucolytic agents such as hypertonic saline solution or recombinant DNase on mucus transport rates or mucus clearance in patients with cystic fibrosis report improvements in both, mucus transport velocities or rates and lung function indices, including FEV1, FVC and FEF25-75 (Amin et al., 2011; Donaldson et al., 2018; Elkins et al., 2006; Laube et al., 1996; McCoy et al., 1996; Quan et al., 2001).
Both MCC and lung function (FEV1, FVC and FEF25-75) improved in cystic fibrosis patients treated with ivacaftor, a CFTR potentiator that increases the channel open probability (Rowe et al., 2014b).
Some studies with mucolytics such as N-acetylcysteine, bromhexine, theophylline/ambroxol or sorebrol demonstrated improved MCC was connected with small improvements in lung function (FEV1, FVC and FEV1/FVC) in patients with chronic bronchitis (Aylward et al., 1980; Castigiioni and Gramolini, 1986; Thomson et al., 1974; Würtemberger et al., 1988).
Uncertainties and Inconsistencies
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
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.
Quantitative Understanding of the Linkage
The available data, though not causally linking decreases in MCC with decreased lung function, provide a good insight into the importance of the physiological role of MCC in maintaining normal lung function. In at least some studies, impairment of MCC correlated with the drop in FEV1 or FEF25-75. Although clinically valuable benefits can be seen in studies with pharmacological agents such as mucolytics and CFTR modifying drugs, they do not cover a wide range of dose responses nor are they supportive of the KER causality. Therefore, we judge our quantitative understanding as moderate.
Response-response Relationship
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).
Time-scale
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
Unknown
Domain of Applicability
The evidences for this KER come from and therefore apply to humans.
References
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