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Relationship: 2448
Title
Motile Cilia Number/Length, Decreased leads to CBF, Decreased
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 via Decreased FOXJ1 | adjacent | Karsta Luettich (send email) | Open for comment. Do not cite |
Taxonomic Applicability
Sex Applicability
| Sex | Evidence |
|---|---|
| Mixed |
Life Stage Applicability
| Term | Evidence |
|---|---|
| All life stages |
Key Event Relationship Description
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
Evidence Supporting this KER
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
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.
Empirical Evidence
Cilia beating frequency analysis in sinusitis patient samples showed a positive correlation between cilia number and CBF (Joki et al., 1998).
Cilia study from patients with recurrent or longstanding respiratory infections demonstrated a correlation between mucociliary transport rate and cilia number, length, and orientation (Toskala et al., 1995).
According to a numerical model formulated by Jayathilake et al., the average periciliary liquid layer (PCL) velocity decreases when cilia are shortened (Jayathilake et al., 2015; Jayathilake et al., 2012).
A study of Chlamydomonas cilia motion concluded that cilia shorter than 4 µm show variable or no periodicity of beating. For cilia longer than 4 µm, the ratio of frequency estimated from body motion to frequency of cilia motion is very close to 1.0, as expected. In short (2 µm, 4 µm) cilia, the ratio was significantly different from 1; apparently, even if the short cilium beats periodically, the frequency of beating is not reliably transmitted to the body motion (Bottier et al., 2018).
In a simulation study by Lee et al., an increase in cilia number increased mucus velocity (Lee et al., 2011).
In zebrafish, deletion or knockdown of FOR20 caused reduced number and length of cilia. Ciliary motility is impaired in animals with reduced FOR20 (Xie et al., 2019).
Cilia beating frequency measurements on normal ciliated or disrupted epithelial strips of tissue revealed lower CBF for tissues with cilia disruptions (Thomas et al., 2009).
Uncertainties and Inconsistencies
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
Unknown
Quantitative Understanding of the Linkage
Cilia beating frequency correlates with cilia size and numbers such that higher number of motile cilia with a healthy length show efficient CBF and a reduction of cilia number and/or length results in a proportionate reduction of CBF. In some studies, mucociliary clearance was measured as an indicator of CBF. Based on evidence presented here, we judge the quantitative understanding to be moderate.
Response-response Relationship
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
No data
Known Feedforward/Feedback loops influencing this KER
Unknown
Domain of Applicability
References
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.