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Event: 1908

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Cilia Beat Frequency, Decreased

Short name

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CBF, Decreased

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Biological Context

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Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Cell term
multi-ciliated epithelial cell

Organ term

Organ term
lung epithelium

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
Abnormal ciliary motility	motile cilium	occurrence

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status
Oxidative stress Leading to Decreased Lung Function	KeyEvent	Karsta Luettich (send email)	Open for comment. Do not cite
Ox stress-mediated CFTR/ASL/CBF/MCC impairment	KeyEvent	Karsta Luettich (send email)	Open for comment. Do not cite
ox stress-mediated FOXJ1/cilia/CBF/MCC impairment	KeyEvent	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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
Homo sapiens	Homo sapiens	High	NCBI
Mus musculus	Mus musculus	High	NCBI
Rattus norvegicus	Rattus norvegicus	Moderate	NCBI
Oryctolagus cuniculus	Oryctolagus cuniculus	High	NCBI
Bos taurus	Bos taurus	High	NCBI
Cavia porcellus	Cavia porcellus	Moderate	NCBI
Lithobates catesbeianus	Rana catesbeiana	High	NCBI

Life Stages

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Life stage	Evidence
All life stages	High

Sex Applicability

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Term	Evidence
Mixed	Moderate

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Cohesive beating of cilia lining the upper and lower respiratory tract is critical for efficient MCC. CBF is influenced by several factors including changes in the physical and chemical properties of the ASL (especially the periciliary fluid), structural modulation in the cilia, concentration of cyclic nucleotides cAMP and cGMP, and intracellular calcium (Ca²⁺). Formation of cyclic nucleotides such as cGMP is mediated by nitric oxide (NO), which is released by an enzyme family of nitric oxide synthases (NOSs) when the substrate L-arginine (L-Arg) is transformed to L-citrulline. NO activates its receptor protein, soluble guanylate cyclase (sGC), which catalyzes formation of cGMP from guanosine triphosphate (GTP). cGMP then activates protein kinase G (PKG) which has been implicated in the regulation of CBF (Jiao et al., 2011; Li et al., 2000). NO-dependent stimulation of CBF has also been associated with an increase in cAMP-dependent protein kinase A (PKA) (Di Benedetto et al., 1991; Lansley et al., 1992; Salathe et al., 1993; Sanderson and Dirksen, 1989; Schmid et al., 2007; Sisson et al., 1999; Uzlaner and Priel, 1999). An increase in intracellular endogenous cAMP was observed after treatment with isobutyl-1-methylxanthine that also increased CBF (Tamaoki et al., 1989). cAMP accumulation in the airway cilia has been shown to be dependent on Ca2+–calmodulin-dependent PDE1A and indirectly regulates CBF (Kogiso et al., 2018). Increase in CBF after treatment with NO substrate, L-arginine and inhibition of CBF by a NOS inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME) further provides evidence for the role of NO in increasing CBF (Jiao J. et al., 2011; Sisson J. H., 1995; Uzlaner and Priel, 1999; Yang et al., 1997). Modulation of CBF is not always accompanied by changes in cAMP levels. PKC activators, phorbol 12-myristate 13-acetate and L-o~-dioctanoylglycerol have been shown to decrease CBF in a concentration- and time-dependent manner in rabbit tracheal epithelial cells (Kobayashi et al., 1989). CBF has been shown to decrease after exposure to inhaled oxidants such as cigarette smoke across different species. A study with 120 subjects showed a significant decrease in nasal CBF following exposure to tobacco smoke (Agius et al., 1998). Exposure to cigarette smoke extract lead to reduction in forskolin-induced CBF in human sinonasal epithelium (Cohen et al., 2009) and isoproterenol- and methacholine-induced CBF in human adenoid tissues (Wang et al., 2012). This decrease in CBF and unresponsiveness to beta-agonist stimulation occurs in parallel to PKC activation and has been shown to be dependent on the duration of exposure to cigarette smoke in mice (Simet et al., 2010). Normal human bronchial epithelial cells exposed to aerosolized nicotine showed decreased CFTR and BK conductance, impaired CBF, ASL volume, and decreased expression of FOXJ1 and KCNMA1 (Garcia-Arcos et al., 2016). A concentration-dependent decrease in CBF has been observed after treatment with aldehydes. For example inhibition of cilia ATPase activity was observed after treatment with acetaldehyde, in ciliated bovine bronchial epithelial cells (Sisson et al., 1991). Acrolein, an aldehyde in the gas phase of cigarette smoke, induced ciliostasis at high concentrations (> 1 mM), after 5 min of treatment, and cellular necrosis after 3 hr. However, at lower concentrations (from 0.5‒1 mM), acrolein transiently reduced the CBF to 4 Hz (Romet et al., 1990).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

There is no standardized method for measuring CBF. Digital high-speed video imaging with a manual count of CBF in slow motion video play is the most commonly used method for CBF measurement (Kim et al., 2011; Peabody et al., 2018). Photometry and video-microscopy have been used to measure CBF in vitro and ex vivo, including in ciliated bovine bronchial epithelial cells (Allen-Gipson et al., 2011; Sisson et al., 2003; Uzlaner and Priel, 1999), normal human bronchial epithelial cells (Feriani et al., 2017), human nasal epithelial cells (Dimova et al., 2005; Min et al., 1999b), human nasal ciliated epithelium (nasal brushings) (Agius et al., 1998), and mouse tracheal rings (Simet et al., 2010). CBF measurement in vitro generally involves mounting the tissue at the air-liquid interface on a stage followed by microscopic analysis and acquisition of images and/or video recordings of beating cilia. For in vivo and ex vivo measurements, Doppler optical coherence tomography (D-OCT) can also be applied, a mesoscopic non-contact imaging modality that provides high-resolution tomographic images and detects micromotion simultaneously (Jing et al., 2017). D-OCT has been used to quantitatively measure CBF in ex vivo rabbit tracheal cultures (Lemieux et al., 2015).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

Age-dependent decreases in CBF have been demonstrated in several species (e.g. guinea pigs, mice, and human) (Bailey et al., 2014; Grubb et al., 2016; Ho et al., 2001; Joki and Saano, 1997; Paul et al., 2013). In a study with 46 healthy subjects with a wide age distribution (mean 42, range 19–81 years), age was found to be negatively associated with airway clearance of inhaled 6-μm Teflon particles (Svartengren et al., 2005).

Female hormones, i.e. progesterone and estrogen, have been shown to have direct effect on CBF, i.e., progesterone reduces CBF, 17β-estradiol and progesterone receptor antagonists counteract progesterone effects, but estradiol alone has also been shown to have no effect on CBF. However, the mechanism by which these hormones modulate CBF is yet to be elucidated (Jain et al., 2012; Jia et al., 2011).

References

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

Agius, A. M., L. A. Smallman, and A. L. Pahor (1998). Age, smoking and nasal ciliary beat frequency. Clin. Otolaryngol. Allied Sci. 23, 227-230.

Allen-Gipson, D.S., Blackburn, M.R., Schneider, D.J., Zhang, H., Bluitt, D.L., Jarrell, J.C., et al. (2011). Adenosine activation of A(2B) receptor(s) is essential for stimulated epithelial ciliary motility and clearance. Am. J. Physiol. Lung Cell. Mol. Physiol. 301, L171-L180.

Bailey, K.L., Bonasera, S.J., Wilderdyke, M., Hanisch, B.W., Pavlik, J.A., Devasure, J., et al. (2014). Aging causes a slowing in ciliary beat frequency, mediated by PKCε. Am. J. Physiol. Lung Cell. Mol. Physiol. 306, L584-L589.

Cohen, N.A., Zhang, S., Sharp, D.B., Tamashiro, E., Chen, B., Sorscher, E.J., et al. (2009). Cigarette smoke condensate inhibits transepithelial chloride transport and ciliary beat frequency. Laryngoscope 119, 2269-2274.

Di Benedetto, G., Manara-Shediac, F.S. and Mehta, A. (1991). Effect of cyclic AMP on ciliary activity of human respiratory epithelium. Eur. Respir. J. 4, 789-795.

Dimova, S., Maes, F., Brewster, M.E., Jorissen, M., Noppe, M. and Augustijns, P. (2005). High-speed digital imaging method for ciliary beat frequency measurement. J. Pharmacy Pharmacol 57, 521-526.

Feriani, L., Juenet, M., Fowler, C.J., Bruot, N., Chioccioli, M., Holland, S.M., et al. (2017). Assessing the Collective Dynamics of Motile Cilia in Cultures of Human Airway Cells by Multiscale DDM. Biophys. J. 113, 109-119.

Garcia-Arcos, I., Geraghty, P., Baumlin, N., Campos, M., Dabo, A.J., Jundi, B., et al. (2016). Chronic electronic cigarette exposure in mice induces features of COPD in a nicotine-dependent manner. Thorax 71, 1119-1129.

Gosepath, J., Schaefer, D., Brommer, C., Klimek, L., Amedee, R.G., and Mann, W.J. (2000). Subacute Effects of Ozone Exposure on Cultivated Human Respiratory Mucosa. Am. J. Rhinol. 14, 411-418.

Grubb, B.R., Livraghi-Butrico, A., Rogers, T.D., Yin, W., Button, B. and Ostrowski, L.E. (2016). Reduced mucociliary clearance in old mice is associated with a decrease in Muc5b mucin. Am. J. Physiol. Lung Cell. Mol. Physiol. 310, L860-L867.

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, 983-988.

Jain, R., Ray, J.M., Pan, J.-H. and Brody, S.L. (2012). Sex hormone-dependent regulation of cilia beat frequency in airway epithelium. Am. J. Respir. Crit. Care Med. 46, 446-453.

Jia, S., Zhang, X., He, D.Z., Segal, M., Berro, A., Gerson, T., et al., 2011. Expression and Function of a Novel Variant of Estrogen Receptor–α36 in Murine Airways. Am. J. Respir. Cell Mol. Biol. 45, 1084-1089.

Jiao, J., Wang, H., Lou, W., Jin, S., Fan, E., Li, Y., et al. (2011). Regulation of ciliary beat frequency by the nitric oxide signaling pathway in mouse nasal and tracheal epithelial cells. Exp. Cell Res. 317, 2548-2553.

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, 8522-8522.

Joki, S. and Saano, V. (1997). Influence of ageing on ciliary beat frequency and on ciliary response to leukotriene D4 in guinea‐pig tracheal epithelium. Clin. Exp. Pharmacol. Physiol. 24, 166-169.

Kim, W., Han, T.H., Kim, H.J., Park, M.Y., Kim, K.S. and Park, R.W. (2011). An Automated Measurement of Ciliary Beating Frequency using a Combined Optical Flow and Peak Detection. J. Healthc. Inform. Res. 17, 111-119.

Knoll, M., Shaoulian, R., Magers, T. and Talbot, P. (1995). Ciliary beat frequency of hamster oviducts is decreased in vitro by exposure to solutions of mainstream and sidestream cigarette smoke. Biol. Reprod. 53, 29-37.

Kobayashi, K., Tamaoki, J., Sakai, N., Chiyotani, A. and Takizawa, T. (1989). Inhibition of ciliary activity by phorbol esters in rabbit tracheal epithelial cells. Lung 167, 277-284.

Kogiso, H., Hosogi, S., Ikeuchi, Y., Tanaka, S., Inui, T., Marunaka, Y., et al. (2018). [Ca(2+) ]i modulation of cAMP-stimulated ciliary beat frequency via PDE1 in airway ciliary cells of mice. Exp. Physiol. 103, 381-390.

Lansley, A.B., Sanderson, M.J. and Dirksen, E.R. (1992). Control of the beat cycle of respiratory tract cilia by Ca2+ and cAMP. Am. J. Physiol. 263, L232-242.

Lemieux, B.T., Chen, J.J., Jing, J., Chen, Z. and Wong, B.J.F. (2015). Measurement of ciliary beat frequency using Doppler optical coherence tomography. Int. Forum Allergy Rhinol. 5, 1048-1054.

Li, D., Shirakami, G., Zhan, X. and Johns, R.A. (2000). Regulation of ciliary beat frequency by the nitric oxide-cyclic guanosine monophosphate signaling pathway in rat airway epithelial cells. Am. J. Respir. Cell Mol. Biol. 23, 175-181.

Min, Y.-G., Ohyama, M., Lee, K.S., Rhee, C.-S., Oh, S.H., Sung, M.-W., et al. (1999). Effects of free radicals on ciliary movement in the human nasal epithelial cells. Auris Nasus Larynx 26, 159-163.

Paul, P., Johnson, P., Ramaswamy, P., Ramadoss, S., Geetha, B. and Subhashini, A.S. (2013). The Effect of Ageing on Nasal Mucociliary Clearance in Women: A Pilot Study. ISRN Pulmonology 2013, 5.

Peabody, J.E., Shei, R.-J., Bermingham, B.M., Phillips, S.E., Turner, B., Rowe, S.M., et al. (2018). Seeing cilia: imaging modalities for ciliary motion and clinical connections. Am. J. Physiol. Lung Cell. Mol. Physiol. 314, L909-L921.

Romet, S., Dubreuil, A., Baeza, A., Moreau, A., Schoevaert, D. and Marano, F. (1990). Respiratory tract epithelium in primary culture: Effects of. Toxicol. In Vitro 4, 399-402.

Salathe, M., Pratt, M.M. and Wanner, A. (1993). Cyclic AMP-dependent phosphorylation of a 26 kD axonemal protein in ovine cilia isolated from small tissue pieces. Am. J. Respir. Cell Mol. Biol. 9, 306-314.

Sanderson, M.J. and Dirksen, E.R. (1989). Mechanosensitive and beta-adrenergic control of the ciliary beat frequency of mammalian respiratory tract cells in culture. Am. Rev. Respir. Dis. 139, 432-440.

Schmid, A., Sutto, Z., Nlend, M.-C., Horvath, G., Schmid, N., Buck, J., et al. (2007). Soluble Adenylyl Cyclase Is Localized to Cilia and Contributes to Ciliary Beat Frequency Regulation via Production of cAMP. J. Gen. Physiol. 130, 99-109.

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, 135.

Simet, S.M., Sisson, J.H., Pavlik, J.A., Devasure, J.M., Boyer, C., Liu, X., et al. (2010). Long-term cigarette smoke exposure in a mouse model of ciliated epithelial cell function. Am. J. Respir. Cell Mol. Biol. 43, 635-640.

Sisson, J.H. (1995). Ethanol stimulates apparent nitric oxide-dependent ciliary beat frequency in bovine airway epithelial cells. Am. J. Physiol. 268, L596-600.

Sisson, J.H., May, K. and Wyatt, T.A. (1999). Nitric oxide-dependent ethanol stimulation of ciliary motility is linked to cAMP-dependent protein kinase (PKA) activation in bovine bronchial epithelium. Alcohol Clin. Exp. Res. 23, 1528-1533.

Sisson, J.H., Stoner, J., Ammons, B. and Wyatt, T. (2003). All‐digital image capture and whole‐field analysis of ciliary beat frequency. J. Microsc. 211, 103-111.

Sisson, J.H., Tuma, D.J. and Rennard, S.I. (1991). Acetaldehyde-mediated cilia dysfunction in bovine bronchial epithelial cells. Am. J. Physiol. 260, L29-36.

Svartengren, M., Falk, R. and Philipson, K. (2005). Long-term clearance from small airways decreases with age. Eur. Respir. J. 26, 609-615.

Tamaoki, J., Kondo, M. and Takizawa, T. (1989). Effect of cAMP on ciliary function in rabbit tracheal epithelial cells. J. Appl. Physiol. 66, 1035-1039.

Uzlaner, N. and Priel, Z. (1999). Interplay between the NO pathway and elevated [Ca(2+)](i) enhances ciliary activity in rabbit trachea. J. Physiol. 516, 179-190.

Wang, L.F., White, D.R., Andreoli, S.M., Mulligan, R.M., Discolo, C.M. and Schlosser, R.J. (2012). Cigarette smoke inhibits dynamic ciliary beat frequency in pediatric adenoid explants. Otolaryngol. Head Neck Surg. 146, 659-663.

Yaghi, A., Zaman, A., Cox, G. and Dolovich, M.B. (2012). Ciliary beating is depressed in nasal cilia from chronic obstructive pulmonary disease subjects. Respir. Med. 106, 1139-1147.

Yang, B., Schlosser, R.J. and Mccaffrey, T.V. (1997). Signal transduction pathways in modulation of ciliary beat frequency by methacholine. Ann. Otol. Rhinol. Laryngol. 106, 230-236.