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Relationship: 2448

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

Motile Cilia Number/Length, Decreased leads to CBF, Decreased

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 via Decreased FOXJ1 adjacent Karsta Luettich (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 Do not cite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
Danio rerio Danio rerio NCBI

Sex Applicability

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

Life Stage Applicability

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

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 cilia in the respiratory epithelium beat in a coordinated fashion at a frequency of approximately 10 to 16 Hz, propelling mucus upwards (Joki et al., 1998; Smith et al., 2012). Many factors, including cilia length, number, structure, orientation as well as mucus viscosity, temperature, pH, chemicals, airway surface liquid height, exposure to bacterial and viral pathogens have been shown to affect ciliary function (Clary-Meinesz et al., 1998; Ho et al., 2001b; Jing et al., 2017; Joki et al., 1998; Kanthakumar et al., 1996; Mall, 2008; Smith et al., 2012; Snyder et al., 2017). Alteration from normal physiological conditions and from healthy cilia number/length/structure typically reduces the cilia beat frequency (CBF) (Clary-Meinesz et al., 1998; Jayathilake et al., 2012).

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 Chlamydomonas, ciliary motion is directly related to the length of the cilia (Bottier et al., 2018). Similar observations have been made in zebrafish, where modulation of cilia length and number by FOR20 (centrosomal protein 20) deletion/knockdown directly impairs ciliary motility (Xie et al., 2019). There is also a positive correlation between cilia number and CBF in sinusitis patients (Joki et al., 1998), while cilia number, length and orientation correlate positively with mucociliary transport rate in patients with recurrent or longstanding respiratory infections (Toskala et al., 1995; Joki et al., 1998). Comparisons of strips of normal and disrupted ciliated epithelium have shown that CBF is decreased in the latter (Thomas et al., 2009). Mathematical models and simulations have shown that periciliary liquid and mucus velocity are directly affected by cilia number and length (Lee et al., 2011; Jayathilake et al., 2012; Jayathilake et al., 2015).  

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

Many research groups have shown positive correlations between cilia number/length and ciliary function in studies dating as early as 1995. In some cases, the authors measured mucociliary clearance as the endpoint, thus the evidence does not describe causality between cilia number/length and CBF. However, the commonly held assumption is that reduced ciliary function, i.e., reduced CBF, leads to decreased mucociliary clearance. Based on the evidence, 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

Although the majority of studies discuss the effect of shorter cilia on ciliary function, there are also reports on longer than normal cilia impairing cilia function (Jayathilake et al., 2015; Li et al., 2014b). A range of factors other than cilia length and number can influence cilia beat frequency. Often a combination of two or more factors affect ciliary function making it difficult to discern the impact of an individual factor on CBF (Toskala et al., 1995; Xie et al., 2019).

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

A study in nasal mucosa samples from sinusitis patients demonstrated that reduced cilia numbers account for decreased CBF. In normally ciliated samples the CBF was 11.2±3.7 Hz, in samples with some ciliated cells CBF was 8.9±6.3 Hz, and in samples with no detectable cilia CBF was 2.1±3.8 Hz (Joki S. et al., 1998).

Patients with recurrent or longstanding respiratory infections were divided into 3 groups based on mucociliary transport rates (MTR). The group with slowest MTR had the biggest number of non-ciliated columnar cells in the nasal mucosa, and the highest number of short and disoriented cilia. Loss of ciliated cells was seen in 50% of specimens with good MTR (7 to 10.8 mm per minute), in 71% with moderate MTR (3 to 6.9 mm per minute) and in 86% with poor MTR (0 to 2.9 mm per minute). The percentages of short cilia were 1% in the first group, 6% in the second, and 10% in the third. In this study, ciliary disorientation also contributed to the low MTR (Toskala et al., 1995).

Jayathilake et al. developed a two-dimensional numerical model for computing how the length of cilia is affecting fluid flow. In the model, the cilia length was reduced by 5%, 15%, 25%, and 35% from 6 µm while other parameters were kept unchanged. The average periciliary layer (PCL) velocity in stream-wise direction decreases when cilia are shortened. When the cilia are shortened by 10%, the average stream-wise PCL velocity is reduced by about 11%, while the average span-wise PCL velocity is reduced by about 62% (Jayathilake et al., 2012). In a similar study by the same group, the length of cilia was defined as 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130% and 140% of the length of the healthy cilia (i.e., 6 µm). The mucus velocity reaches its maximum value when the ciliary length is around the length of the healthy cilia (or standard length of 6 µm) (Jayathilake et al., 2015).

Cilia shorter than 4 µm have anomalies in the ciliary beating periodicity. Cilia shorter than 2 µm were never found to beat periodically. Cilia between 2 and 4 µm in length exhibited more variable periodicity. Cilia with lengths between 4 and 12 µm beat periodically with conserved frequency (Bottier et al., 2018).

Mucus velocity increased in concordance with cilia number increase. Mean mucus velocity increased from 26.82 µm/s to 49.53 µm/s when cilia number grew from 10 to 24 (Lee et al., 2011).

FOR20 deletion or knockdown in zebrafish reduced the number and length of cilia. Cilia in FOR20 morphants had impaired ciliary motility. When cilia length was reduced from an average 5.5 µm to an average 3 µm due to FOR20 depletion, about 80% cilia displayed consistently paralyzed or arrhythmically beating pattern (Xie et al., 2019).

Nasal brush biopsy samples from pediatric patients with primary ciliary dyskinesia were analyzed. The median CBF was 13.4 Hz for normal ciliated epithelia, 11.4 Hz for the ciliated edge with minor projections and 8.7 Hz for the ciliated edge with major projections (Thomas et al., 2009).

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

Bottier, M., Thomas, K., Dutcher, S., and Bayly, P. (2018). (Preprint) How does cilium length affect beating? bioRxiv, 474346. 

Clary-Meinesz, C., Mouroux, J., Cosson, J., Huitorel, P., and Blaive, B. (1998). Influence of external pH on ciliary beat frequency in human bronchi and bronchioles. Eur. Respir. J. 11(2), 330-333.

Ho, J.C., Chan, K.N., Hu, W.H., Lam, W.K., Zheng, L., Tipoe, G.L., et al. (2001). The Effect of Aging on Nasal Mucociliary Clearance, Beat Frequency, and Ultrastructure of Respiratory Cilia. Am. J. Respir. Crit. Care Med. 163(4), 983-988.

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. 

Jayathilake, P.G., Tan, Z., Le, D.V., Lee, H.P., and Khoo, B.C. (2012). Three-dimensional numerical simulations of human pulmonary cilia in the periciliary liquid layer by the immersed boundary method. Comput. Fluids 67, 130-137.

Jing, J.C., Chen, J.J., Chou, L., Wong, B.J.F., and Chen, Z. (2017). Visualization and Detection of Ciliary Beating Pattern and Frequency in the Upper Airway using Phase Resolved Doppler Optical Coherence Tomography. Sci. Rep. 7(1), 8522-8522. 

Joki, S., Toskala, E., Saano, V., and Nuutinen, J. (1998). Correlation between ciliary beat frequency and the structure of ciliated epithelia in pathologic human nasal mucosa. Laryngoscope 108(3), 426-430. 

Kanthakumar, K., Taylor, G., Cundell, D., Dowling, R., Johnson, M., Cole, P., et al. (1996). The effect of bacterial toxins on levels of intracellular adenosine nucleotides and human ciliary beat frequency. Pulm. Pharmacol. 9(4), 223-230.

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.

Li, Y.Y., Li, C.W., Chao, S.S., Yu, F.G., Yu, X.M., Liu, J., et al. (2014). Impairment of cilia architecture and ciliogenesis in hyperplastic nasal epithelium from nasal polyps. J. Allergy Clin. Immunol. 134, 1282-1292. 

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, 13-24.

Smith, C.M., Djakow, J., Free, R.C., Djakow, P., Lonnen, R., Williams, G., et al. (2012). ciliaFA: a research tool for automated, high-throughput measurement of ciliary beat frequency using freely available software. Cilia 1, 14. 

Snyder, R.J., Hussain, S., Tucker, C.J., Randell, S.H., and Garantziotis, S. (2017). Impaired Ciliogenesis in differentiating human bronchial epithelia exposed to non-Cytotoxic doses of multi-walled carbon Nanotube. Part. Fibre Toxicol. 14, 1-14. 

Thomas, B., Rutman, A., and O'Callaghan, C. (2009). Disrupted ciliated epithelium shows slower ciliary beat frequency and increased dyskinesia. Eur. Respir. J. 34, 401-404. 

Toskala, E., Nuutinen, J., Rautiainen, M., and Torkkeli, T. (1995). The correlation of mucociliary transport and scanning electron microscopy of nasal mucosa. Acta Otolaryngol. 115, 61-65. 

Xie, S., Jin, J., Xu, Z., Huang, Y., Zhang, W., Zhao, L., et al. (2019). Centrosomal protein FOR20 is essential for cilia-dependent development in zebrafish embryos. FASEB J. 33, 3613-3622.