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Relationship: 2444

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

ASL Height, Decreased leads to Mucus Viscosity, Increased

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

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
Rattus norvegicus Rattus norvegicus NCBI
Sus scrofa Sus scrofa NCBI
Mustela furo Mustela putorius furo NCBI

Sex Applicability

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

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages Low

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

The phenomenon of ASL volume changes determining mucus viscosity is well described in the cystic fibrosis literature. In patients with this genetic defect, impaired CFTR function results in ASL depletion and mucus hyperviscosity. Mechanistically, the imbalance of Cl and HCO3 secretion and increased Na+ absorption by the airway epithelium results in dehydration of airway mucus, making it more viscous and adhesive (Knowles and Boucher, 2002; Mall et al., 2004; Puchelle et al., 2002; Tarran, 2004). Studies with transgenic mice overexpressing βENaC in the airways corroborate the link between ASL hydration and mucociliary impairment as evidenced by the increased incidence of airway mucus plugging (Mall et al., 2004; Mall, 2008).  Increased mucus viscosity may also play a significant role in asthma and chronic bronchitis, although the mechanisms are less well explored. In a ferret model of cigarette smoke-induced COPD, Lin et al. identified ASL depletion as one of the drivers of increased mucus viscosity and decreased MCC (Lin et al., 2020). The authors also showed that mucus from COPD patients, obtained from 3D organotypic airway epithelial cultures from different smoking donors with COPD, was significantly more viscous than that of healthy, non-smoking individuals and smokers without disease (Lin et al., 2020). Considering the known effects of cigarette smoke exposure on the ASL height (Hassan et al., 2014; Lambert et al., 2014; Raju et al., 2016; Schmid et al., 2015; Xu et al., 2015), this links decreased ASL height to increased mucus viscosity in the context of chronic bronchitis.   

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

In patients with cystic fibrosis, impaired CFTR function results in ASL depletion and mucus hyperviscosity (Knowles and Boucher, 2002; Puchelle et al., 2002; Mall et al., 2004; Tarran, 2004). This has been confirmed experimentally in pig and rat models of this disease (Birket et al., 2014; Birket et al., 2016; Birket et al., 2018). Studies with transgenic mice overexpressing βENaC in the airways also corroborate the link between ASL dehydration and increased mucus viscosity, evidenced by the increased incidence of airway mucus plugging [129, 195]. In a ferret model of cigarette smoke-induced COPD, ASL depletion was shown to be one of the drivers of increased mucus viscosity and decreased MCC (Lin et al., 2020). The same study also showed that mucus from COPD patients, obtained from 3D organotypic airway epithelial cultures from different smoking donors with COPD, is significantly more viscous than that from healthy, non-smoking individuals and smokers without disease (Lin et al., 2020).

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

There are only few studies that report ASL height and mucus viscosity, and although studies on cystic fibrosis in animal models or human cell cultures show the dependencies between these two KEs, the causal evidence is sparse. However, because the underlying mechanism is well-described and translatable across different species and is amenable to positive modulation by e.g. CFTR drugs, we consider the biological plausibility of this KER to be 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

At least one study in primary cultures of human bronchial epithelial cells grown at the air-liquid interface found mucus viscosity to be higher in cultures from cystic fibrosis donors compared to those from healthy donors, but did not observe differences in ASL height (Derichs et al., 2011). In asthmatics, airway mucus is very viscous, and its viscosity increases even more in acute exacerbations (Innes et al., 2009). However, unlike in individuals with cystic fibrosis or chronic bronchitis, changes in ASL height because of impaired anion transport might not be the primary cause for increased mucus viscosity in patients with asthma. Instead a more acidic ASL may lead to improper unpacking of secreted mucins and tethering of mucins to the epithelial surface, where they form protein tangles that result in mucus airway plugs (Abdullah et al., 2017; Bonser and Erle, 2017; Bonser et al., 2016; Evans et al., 2015; Shimura et al., 1988; Tang et al., 2016). Alternatively, the composition of mucus may be altered by production of more acidic mucins thereby skewing the pH balance of mucus itself (Gearhart and Schlesinger, 1989; Holma, 1989; Kim et al., 2014). In addition, mucus viscosity is also affected by the presence of DNA, lipids and proteins other than mucins, such as lactoferrin, albumin and immunoglobulins, all of which may be present in higher amounts in the presence of airway inflammation (Puchelle et al., 2002; Rogers, 2004). 

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

Unknown

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

In primary human bronchial epithelial cultures grown at the air-liquid interface, the ASL depth of cystic fibrosis cells was significantly lower than that of non-cystic fibrosis cells (2.4±0.6 µm vs. 6.7±0.2 µm) and mucus viscosity was significantly higher (80.6±26.5 cP vs. 12.0±3.6 mm/min) by particle-tracking microrheology. FRAP indicated an increased half-life of fluorescence recovery (evidence of increased viscosity) of approx. 16 s in cystic fibrosis cultures vs ca. 11 s in non-cystic fibrosis cultures (Birket et al., 2014).

ASL height in the tracheas of -/- CFTR piglets was significantly lower than in wild-type littermates (3.2±0.8 µm vs. 6.5±0.2 µm) and mucus viscosity was significantly higher by FRAP, which indicated an increased half-life of approx. 13 s in CFTR-deficient tracheas vs ca. 9.5 s in wild-type controls (Birket et al., 2014). Treatment of normal adult pig trachea with 100 µM bumetanide to block HCO3 transport reduced ASL height from 7.8±0.5 µm (untreated) to 6.4±0.4 µm and mucus viscosity from approx. 600 cP (untreated) to 2000 cP at frequencies between 0.5 and 10 Hz (Birket et al., 2014).

In tracheas of Cftr-deficient rats, ASL depths were diminished in both basal and stimulated conditions, from weaning until at least 6 months of age (WT 1 month 22.9 ± 4.6 μm, 6 months 43.6 ± 12.5 μm vs. KO 1 month 6.9 ± 0.7 μm, 6 month 19.5 ± 4.8 μm). Under baseline conditions at 1 month of age, effective viscosity was no different in KO tracheae compared with WT tracheae (1.76 ± 1.0 cP WT vs. 1.90 ± 1.7 cP KO). At 3 months, effective viscosity of KO airway mucus increased slightly but was still no different than that of WT airway mucus (5.12 ± 1.0 cP WT vs. 10.72 ± 2.7 cP KO). By 6 months of age, KO tracheal mucus was 20-fold more viscous compared with WT littermates (2.91 ± 0.9 cP WT vs. 65.09 ± 3.6 cP KO) (Birket et al., 2018).

Treatment of primary bronchial epithelial cell monolayer cultures from G551D/F508del cystic fibrosis patients with ivacaftor, a CFTR potentiator, at concentrations ≥ 100 nM for 24 h increased ASL height from ca. 6 to 17.5 µm, which was similar to the ASL height of non-cystic fibrosis cultures (18.03 ± 1.6 µm). The half-life of time to recovery measured by FRAP shortened from 12.39 ± 1.3 to 7.57 ± 0.8 s, indicative of decreased mucus viscosity. Effective viscosity of cells treated with ivacaftor (600 cP) was significantly lower than control (2,600 cP) at the physiological frequency of 0.9 Hz (Birket et al., 2016).

Treatment of primary bronchial epithelial cell monolayer cultures from homozygous F508del cystic fibrosis patients with the combination of 10 µM ivacaftor and 3 µM C18 (a ivacaftor homolog) with 20 µM forskolin significantly increased ASL height (23.4 ±  2.6 vs. 9.01 ± 1.4 µm C18 + forskolin, 10.99 ± 1.7 µm ivacaftor + forskolin; 13.03 ± 2.8 µm forskolin alone, and 12.53 ± 2.3 µm vehicle). Effective mucus viscosity effective in situ was reduced from ca. 1200 cP (vehicle) to ca. 100 cP by 48-h treatment only with the combination of ivacaftor and C18 (Birket et al., 2016).

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

No data

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

Unknown

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

References

List of the literature that was cited for this KER description. More help
  • Abdullah, L.H., Evans, J.R., Wang, T.T., Ford, A.A., Makhov, A.M., Nguyen, K., et al. (2017). Defective postsecretory maturation of MUC5B mucin in cystic fibrosis airways. JCI Insight 2(6), e89752. 
  • Birket, S.E., Chu, K.K., Houser, G.H., Liu, L., Fernandez, C.M., Solomon, G.M., et al. (2016). Combination therapy with cystic fibrosis transmembrane conductance regulator modulators augment the airway functional microanatomy. Am. J. Physiol. Lung Cell. Mol. Physiol. 310(10), L928-L939.
  • Birket, S.E., Chu, K.K., Liu, L., Houser, G.H., Diephuis, B.J., Wilsterman, E.J., et al. (2014). A functional anatomic defect of the cystic fibrosis airway. Am. J. Respir. Crit. Care Med. 190(4), 421-432.
  • Birket, S.E., Davis, J.M., Fernandez, C.M., Tuggle, K.L., Oden, A.M., Chu, K.K., et al. (2018). Development of an airway mucus defect in the cystic fibrosis rat. JCI Insight 3(1). e97199.
  • Bonser, L.R., and Erle, D.J. (2017). Airway mucus and asthma: the role of MUC5AC and MUC5B. Journal of clinical medicine 6(12), 112.
  • Bonser, L.R., Zlock, L., Finkbeiner, W., and Erle, D.J. (2016). Epithelial tethering of MUC5AC-rich mucus impairs mucociliary transport in asthma. J Clin Invest 126(6), 2367-2371. 
  • Derichs, N., Jin, B.-J., Song, Y., Finkbeiner, W.E., and Verkman, A.S. (2011). Hyperviscous airway periciliary and mucous liquid layers in cystic fibrosis measured by confocal fluorescence photobleaching. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 25(7), 2325-2332. 
  • Evans, C.M., Raclawska, D.S., Ttofali, F., Liptzin, D.R., Fletcher, A.A., Harper, D.N., et al. (2015). The polymeric mucin Muc5ac is required for allergic airway hyperreactivity. Nat Commun 6, 6281. 
  • Gearhart, J.M., and Schlesinger, R.B. (1989). Sulfuric acid-induced changes in the physiology and structure of the tracheobronchial airways. Environmental health perspectives 79, 127-136. 
  • Hassan, F., Xu, X., Nuovo, G., Killilea, D.W., Tyrrell, J., Da Tan, C., et al. (2014). Accumulation of metals in GOLD4 COPD lungs is associated with decreased CFTR levels. Respir. Res. 15(1), 69.
  • Holma, B. (1989). Effects of inhaled acids on airway mucus and its consequences for health. Environmental health perspectives 79, 109-113. 
  • Innes, A.L., Carrington, S.D., Thornton, D.J., Kirkham, S., Rousseau, K., Dougherty, R.H., et al. (2009). Ex vivo sputum analysis reveals impairment of protease-dependent mucus degradation by plasma proteins in acute asthma. American journal of respiratory and critical care medicine 180(3), 203-210.
  • Jayathilake, P.G., Le, D.V., Tan, Z., Lee, H.P., and Khoo, B.C. (2015). A numerical study of muco-ciliary transport under the condition of diseased cilia. Comput. Methods Biomech. Biomed. Engin. 18(9), 944-951. 
  • Kim, D., Liao, J., and Hanrahan, J.W. (2014). The buffer capacity of airway epithelial secretions. Frontiers in Physiology 5(188). doi: 10.3389/fphys.2014.00188.
  • Knowles, M.R., and Boucher, R.C. (2002). Mucus clearance as a primary innate defense mechanism for mammalian airways. J. Clin. Investig. 109(5), 571-577.
  • Lambert, J.A., Raju, S.V., Tang, L.P., McNicholas, C.M., Li, Y., Courville, C.A., et al. (2014). Cystic fibrosis transmembrane conductance regulator activation by roflumilast contributes to therapeutic benefit in chronic bronchitis. Am. J. Respir. Cell Mol. Biol. 50(3), 549-558.
  • Lee, W., Jayathilake, P., Tan, Z., Le, D., Lee, H., and Khoo, B. (2011). Muco-ciliary transport: effect of mucus viscosity, cilia beat frequency and cilia density. Comput. Fluids 49(1), 214-221.
  • Lin, V.Y., Kaza, N., Birket, S.E., Kim, H., Edwards, L.J., LaFontaine, J., et al. (2020). Excess mucus viscosity and airway dehydration impact COPD airway clearance. Eur. Respir. J. 55(1), 1900419. 
  • Lorenzi, G., Böhm, G., Guimarães, E., Vaz, C., King, M., and Saldiva, P. (1992). Correlation between rheologic properties and in vitro ciliary transport of rat nasal mucus. Biorheology 29(4), 433-440.
  • Mall, M.A. (2008). Role of cilia, mucus, and airway surface liquid in mucociliary dysfunction: lessons from mouse models. J. Aerosol Med. Pulm. Drug Deliv. 21(1), 13-24.
  • Mall, M., Grubb, B.R., Harkema, J.R., O'Neal, W.K., and Boucher, R.C. (2004). Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice. Nat. Med. 10(5), 487.
  • Puchelle, E., Bajolet, O., and Abély, M. (2002). Airway mucus in cystic fibrosis. Paediatr. Respir. Rev. 3(2), 115-119. 
  • Raju, S.V., Lin, V.Y., Liu, L., Mcnicholas, C.M., Karki, S., Sloane, P.A., et al. (2016). The Cftr Potentiator Ivacaftor Augments Mucociliary Clearance Abrogating Cftr Inhibition by Cigarette Smoke. Am. J. Respir. Cell Mol. Biol. 56(1), 99-108.
  • Rogers, D.F. (2004). Airway mucus hypersecretion in asthma: an undervalued pathology? Current opinion in pharmacology 4(3), 241-250.
  • Schmid, A., Baumlin, N., Ivonnet, P., Dennis, J.S., Campos, M., Krick, S., et al. (2015). Roflumilast partially reverses smoke-induced mucociliary dysfunction. Respir. Res. 16(1), 135. 
  • Shimura, S., Sasaki, T., Sasaki, H., and Takishima, T. (1988). Chemical properties of bronchorrhea sputum in bronchial asthma. Chest 94(6), 1211-1215.
  • Tang, X.X., Ostedgaard, L.S., Hoegger, M.J., Moninger, T.O., Karp, P.H., McMenimen, J.D., et al. (2016). Acidic pH increases airway surface liquid viscosity in cystic fibrosis. J Clin Invest 126(3), 879-891. 
  • Tarran, R. (2004). Regulation of airway surface liquid volume and mucus transport by active ion transport. Proc. Am. Thorac. Soc. 1(1), 42-46.
  • Xu, X., Balsiger, R., Tyrrell, J., Boyaka, P.N., Tarran, R., and Cormet-Boyaka, E. (2015). Cigarette smoke exposure reveals a novel role for the MEK/ERK1/2 MAPK pathway in regulation of CFTR. Biochim. Biophys. Acta 1850(6), 1224-1232.