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Event: 1909

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Mucociliary Clearance, Decreased

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
MCC, Decreased

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). 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 signalling 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. More help
Process Object Action
mucociliary clearance trait decreased

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 OECD Status
Oxidative stress [MIE] Leading to Decreased Lung Function [AO] KeyEvent Karsta Luettich (send email) Open for comment. Do not cite
Ox stress-mediated CFTR/ASL/CBF/MCC impairment KeyEvent Karsta Luettich (send email) Under development: Not open for comment. Do not cite

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. 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
Sus scrofa domesticus Sus scrofa domesticus Moderate NCBI
Ovis aries Ovis aries Moderate NCBI
Cavia porcellus Cavia porcellus Moderate NCBI
Canis lupus Canis lupus Moderate NCBI
Rana catesbeiana Rana catesbeiana Moderate NCBI
Oryctolagus cuniculus Oryctolagus cuniculus Moderate NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help
Life stage Evidence
All life stages High

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Term Evidence
Mixed High

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. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

In healthy adults, tracheal mucus movement varies from 4 to >20 mm/min (Stannard and O'Callaghan, 2006), whereas mucociliary clearance (MCC) in the small airways is slower due to the lower number of ciliated cells (fewer cilia) and their shorter length (Foster et al., 1980; Iravani, 1969; Wanner et al., 1996). Since optimal MCC is dependent in multiple factors, including cilia number and structure as well as ASL and mucus properties, any disturbances of these can lead to impaired MCC. While high humidity or infection can enhance MCC, long-term exposure to noxious substances (e.g. cigarette smoke) lead to decreased mucus clearance from the airways. In most instances this is reflected by decreased mucus transport rates or velocities.  

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. 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).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

In humans, MCC has been assessed traditionally following inhalation of radio-labeled particles such as 99Tcm-labeled polystyrene particles, resin particles or serum albumin and following their clearance at regular intervals by radioimaging using gamma cameras (Agnew et al., 1986; Kärjä et al., 1982). Taking into account inhalation volumes and flow rates, lung airflow, particle deposition and retention, clearance rates can be calculated and effects of e.g. drugs on MCC can be examined. Alternatively, since MCC occurs at a similar rate in the nose to that in trachea and bronchi (Andersen and Proctor, 1983; Rutland and Cole, 1981) and for ease of use, measurements of MCC can be restricted to that of nasal MCC only. Probably one of the simplest methods is the saccharin transit test (STT). For this test, a small particle of saccharin is placed behind the anterior end of the inferior turbinate. The saccharin will be transported by mucociliary action toward the nasopharynx, where its sweet taste is perceived. When MCC is impaired, saccharin transit times will increase, with a 10- to 20-minute delay being considered a clinical sign of decreased MCC. Using the same principle, the test can also be performed or complemented with dyes such as indigo carmine or methylene blue (Deborah and Prathibha, 2014).

In experimental animals, MCC has been evaluated by gamma-scintigraphy (Greiff et al., 1990; Hua et al., 2010; Read et al., 1992), fluorescence videography/fluoroscopy (in explanted tracheas etc.) (Grubb et al., 2016; Rogers  et al., 2018), or by 3D-SPECT (Ortiz Belda et al., 2016). Direct observation of particle movement across airway epithelia to determine mucus velocity or transport rates by using a fiberoptic bronchoscope may be helpful when working in larger animals such as dogs (King, 1998). In vitro, freshly excised frog palate preparations have been used to assess cilia function and mucociliary transport by videomicroscopy (Macchione et al., 1995; Macchione et al., 1999; Trindade et al., 2007). Murine and human nasal, bronchial and small airway epithelial models grown at the air-liquid interface are also suitable in vitro test systems for determining mucus transport by tracing inert particle movement with a set-up similar to that used for assessing CBF (Benam et al., 2018; Fliegauf et al., 2013; Knowles and Boucher, 2002; Sears et al., 2015).  

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

Evidence for Perturbation by Stressor

Sulfur dioxide

SO2 exposure of dogs dose-dependently decreased CBF and also caused a marked decrease in mean bronchial mucociliary clearance (from 53.7 ± 5.7% to 32.8 ± 7.7%) after 90 min (Yeates et al., 1997). In guinea pig tracheas, SO2 exposure affected CBF, albeit non-significantly, and mucociliary activity (Knorst et al., 1994).

Formaldehyde

Treatment of frog palate epithelium with different concentrations of formaldehyde induced significant decreases in CBF and MCC (Fló-Neyret et al., 2001; Morgan et al., 1984). Exposure of F344 rats to formaldehyde caused epithelial adaptation of the nasal epithelium, effectively reducing the number of ciliated cells (and hence cilia beating activity) through squamous metaplasia. At the same time, formaldehyde exposure resulted in “ciliastasis” or loss of ciliary activity in a concentration- and exposure duration-dependent manner as well as in a slowing of mucus flow rates (Morgan et al., 1986). 

PM10

Incubation of frog palates with PM10 from Sao Paolo, Brazil, for up to 120 min decreased mucociliary transport at concentrations ≥1000 pg/m3 (Macchione et al., 1999).

Nitric oxide

In New Zealand white rabbits exposed to 3 ppm NO2 for 24 h, the average CBF decreased from 764 beats/min to 692 beats/min and the transport velocity decreased from 5.23 mm/min to 3.03 mm/min (Kakinoki, 1998).

Ozone

Acute exposure (2 h) of adult ewes to 1.0 ppm ozone significantly reduced tracheal mucus transport velocity (TMV) at 40 min and 2 h post-exposure. Repeated exposure to 1.0 ppm ozone for 5 hper day, for 4 consecutive days showed a progressively significant decrease in TMV on the first and second days, and stabilized over the third and fourth days, around values ranging from -42% to -55% of the initial baseline. TMV remained depressed even after the end of exposure, persisting up to 5 days post-exposure (Allegra et al., 1991).  

Cigarette smoke

Nasomuciliary clearance time (determined by saccharin transit test) was significantly higher in smokers than in non-smokers 8 h after smoking (16 ± 6 min vs 10 ± 4 min) and insignicantly higher immediately after smoking (11 ± 6 min vs 10 ± 4 min). Nasomuciliary clearance time correlated positively with cigarettes per day and packs/year index (Proença et al., 2011).

In a small Indian cross-sectional study, the mean nasomuciliary clearance (determined by saccharin transit test) in smokers was significantly higher than that of nonsmokers (481.2 ± 29.83 s vs 300.32 ± 17.4 s). In addition, mean nasomuciliary clearance increased as the duration of smoking increased (NMC in smoking <1 year = 492.25 ± 79.93 s, NMC in smoking for 1-5 years = 516.7 ± 34.01 s, and NMC in smoking >5 years = 637.5 ± 28.49 s) (Baby et al., 2014).

Nasomuciliary clearance (determined by saccharin transit test) in active and passive smokers was significantly higher than in non-smokers (23.08 ± 4.60 min; 20.31 ± 2.51 min vs 8.57 ± 2.12 min) (Yadav et al., 2014).

Nasomuciliary clearance (determined by saccharin transit test) was significantly higher in active smokers than in passive smokers and non-smokers (23.59 ± 12.41 min vs 12.6 ± 4.67 min; 6.4 ± 1.55 min) (Habesoglu et al., 2012).

Nasomuciliary clearance time (determined by saccharin transit test) in smokers was significantly higher than in former smokers and non-smokers (15.6 min vs 11.77 min and 11.71 min, respectively) (Pagliuca et al., 2015).

Moderate and heavy smokers had higher saccharin transit test times than light smokers and non-smokers, and there was a positive correlation between STT and cigarettes/day (Xavier et al., 2013).

The median nasal mucociliary clearance time (determined by saccharin transit test) was significantly higher in smokers (who smoked a mean of 20.6 cigarettes (median: 20) per day) than in  nonsmokers (12 (interquartile range: 5–33) min vs 9 (interquartile range: 4–12) min) (Dülger et al., 2018). 

Nasal mucociliary clearance time (determined by saccharin transit test) in smokers was significantly higher than in non-smokers (536.19 ± 254.81 s vs 320.43 ± 184.98 s) and correlated with the numbers of cigarettes per day, pack-years and smoking duration (Solak et al., 2018).

Current smokers had a median (IQR) mucociliary clearance transit time (determined by saccharin transit test) of 13.15 (9.89–16.08) min, which was significantly longer compared with that of never smokers at 7.24 (5.73–8.73) min, former smokers at 7.26 (6.18–9.17) min, exclusive e-cigarette users at 7.00 (6.38–9.00) min, and exclusive heated tobacco product users at 8.00 (6.00–8.00) min (Polosa et al., 2021).

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help

Agnew, J., Sutton, P., Pavia, D. and Clarke, S. (1986). Radioaerosol assessment of mucociliary clearance: towards definition of a normal range. Brit. J. Radiol. 59, 147-151.

Allegra, L., Moavero, N., and Rampoldi, C. (1991). Ozone-induced impairment of mucociliary transport and its prevention with N-acetylcysteine. Am. J. Med. 91, S67-S71.

Andersen, I. and Proctor, D. (1983). Measurement of nasal mucociliary clearance. Eur. J. Respir. Dis. Suppl. 127, 37-40.

Baby, M.K., Muthu, P.K., Johnson, P., and Kannan, S. (2014). Effect of cigarette smoking on nasal mucociliary clearance: A comparative analysis using saccharin test. Lung India 31, 39-42. 

Benam, K.H., Vladar, E.K., Janssen, W.J. and Evans, C.M. (2018). Mucociliary defense: emerging cellular, molecular, and animal models. Ann. Am. Thorac. Soc. 15, S210-S215.

Deborah, S. and Prathibha, K., 2014. Measurement of nasal mucociliary clearance. Clin. Res. Pulmonol. 2, 1019.

Dülger, S., Akdeniz, Ö., Solmaz, F., Şengören Dikiş, Ö., and Yildiz, T. (2018). Evaluation of nasal mucociliary clearance using saccharin test in smokers: A prospective study. Clin. Respir. J. 12, 1706-1710. 

Fliegauf, M., Sonnen, A.F.P., Kremer, B. and Henneke, P. (2013). Mucociliary Clearance Defects in a Murine In Vitro Model of Pneumococcal Airway Infection. PloS ONE 8, e59925.

Fló-Neyret, C., Lorenzi-Filho, G., Macchione, M., Garcia, M.L.B. and Saldiva, P.H.N. (2001). Effects of formaldehyde on the frog's mucociliary epithelium as a surrogate to evaluate air pollution effects on the respiratory epithelium. Braz. J. Med. Biol. Res. 34, 639-643.

Foster, W., Langenback, E. and Bergofsky, E. (1980). Measurement of tracheal and bronchial mucus velocities in man: relation to lung clearance. J. Appl. Physiol. 48, 965-971.

Greiff, L., Wollmer, P., Erjefält, I., Pipkorn, U. and Persson, C. (1990). Clearance of 99mTc DTPA from guinea pig nasal, tracheobronchial, and bronchoalveolar airways. Thorax 45, 841-845.

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.

Habesoglu, M., Demir, K., Yumusakhuylu, A.C., Sahin Yilmaz, A., and Oysu, C. (2012). Does passive smoking have an effect on nasal mucociliary clearance? Otolaryngol Head Neck Surg. 147, 152-156.

Hua, X., Zeman, K.L., Zhou, B., Hua, Q., Senior, B.A., Tilley, S.L., et al. (2010). Noninvasive real-time measurement of nasal mucociliary clearance in mice by pinhole gamma scintigraphy. J. Appl. Physiol. 108, 189-196.

Iravani, J. (1969). Zum Mechanismus der Ortsabhängigkeit der Flimmeraktivität im Bronchialbaum/Location-Dependent Activity of the Ciliary Movement in the Bronchial Tree and its Possible Mechanism. In: Habermann E. et al. (eds) Naunyn Schmiedebergs Archiv für Pharmakologie. Springer, Berlin, Heidelberg.

Kakinoki Y, Ohashi Y, Tanaka A, Washio Y, Yamada K, Nakai Y, Morimoto K. (1998). Nitrogen dioxide compromises defence functions of the airway epithelium. Acta Oto-Laryngol. 118, 221-226.

Kärjä, J., Nuutinen, J. and Karjalainen, P. (1982). Radioisotopic Method for Measurement of Nasal Mucociliary Activity. Arch. Otolaryngol. 108, 99-101.

King, M. (1998). Experimental models for studying mucociliary clearance. Eur. Respir. J. 11, 222-228.

Knorst, M.M., Kienast, K., Riechelmann, H., Müller-Quernheim, J. and Ferlinz, R. (1994). Effect of sulfur dioxide on mucociliary activity and ciliary beat frequency in guinea pig trachea. Int. Arch. Occup. Environm. Health 65, 325-328.

Knowles, M.R. and Boucher, R.C. (2002). Mucus clearance as a primary innate defense mechanism for mammalian airways. J. Clin. Invest. 109, 571-577.

Macchione, M., Guimarães, E., Saldiva, P. and Lorenzi-Filho, G. (1995). Methods for studying respiratory mucus and mucus clearance. Braz. J. Med. Biol Res. 28, 1347.

Macchione, M., Oliveira, A.P., Gallafrio, C.T., Muchão, F.P., Obara, M.T., Guimarães, E.T., et al. (1999). Acute effects of inhalable particles on the frog palate mucociliary epithelium. Environm. Health Persp. 107, 829-833.

Morgan, K., Patterson, D. and Gross, E. (1986). Responses of the nasal mucociliary apparatus of F-344 rats to formaldehyde gas. Toxicol. Appl. Pharmacol. 82, 1-13.

Morgan, K.T., Patterson, D.L. and Gross, E.A. (1984). Frog palate mucociliary apparatus: structure, function, and response to formaldehyde gas. Fund. Appl. Toxicol. 4, 58-68.

Ortiz Belda, J.L., Ortiz, A., Milara Payá, J., Armengot Carceller, M., Sanz García, C., Compañ Quilis, D., et al. (2016). Evaluation of Mucociliary Clearance by Three Dimension Micro-CT-SPECT in Guinea Pig: Role of Bitter Taste Agonists. Plos ONE 11, e0164399.

Pagliuca, G., Rosato, C., Martellucci, S., De Vincentiis, M., Greco, A., Fusconi, M., et al. (2015). Cytologic and functional alterations of nasal mucosa in smokers: temporary or permanent damage? Otolaryngol Head Neck Surg 152, 740-745.

Proença, M., Xavier, R.F., Ramos, D., Cavalheri, V., Pitta, F., and Ramos, E.C. (2011). Immediate and short term effects of smoking on nasal mucociliary clearance in smokers. Revista Portuguesa de Pneumologia (English Edition) 17), 172-176.

Read, R.C., Roberts, P., Munro, N., Rutman, A., Hastie, A., Shryock, T., et al. (1992). Effect of Pseudomonas aeruginosa rhamnolipids on mucociliary transport and ciliary beating. J. Appl. Physiol. 72, 2271-2277.

Rogers, T.D., Ostrowski, L.E., Livraghi-Butrico, A., Button, B. and Grubb, B.R., 2018. Mucociliary clearance in mice measured by tracking trans-tracheal fluorescence of nasally aerosolized beads. Sci. Rep. 8, 1-12.

Rutland, J. and Cole, P.J. (1981). Nasal mucociliary clearance and ciliary beat frequency in cystic fibrosis compared with sinusitis and bronchiectasis. Thorax 36, 654-658.

Sears, P.R., Yin, W.-N. and Ostrowski, L.E. (2015). Continuous mucociliary transport by primary human airway epithelial cells in vitro. Am. J. Physiol. Lung Cell. Mol. Physiol. 309, L99-L108.

Solak, I., Marakoglu, K., Pekgor, S., Kargin, N.C., Alataş, N., and Eryilmaz, M.A. (2018). Nasal mucociliary activity changes in smokers. Konuralp Med. J. 10, 269-275.

Stannard, W. and O'callaghan, C. (2006). Ciliary function and the role of cilia in clearance. J. Aerosol Med. 19, 110-115.

Trindade, S.H.K., De Mello Júnior, J.F., De Godoy Mion, O., Lorenzi-Filho, G., Macchione, M., Guimarães, E.T., et al. (2007). Methods for Studying Mucociliary Transport. Braz. J. Otorhinolaryngol. 73, 704-712.

Wanner, A., Salathe, M. and O'riordan, T.G. (1996). Mucociliary clearance in the airways. Am. J. Respir. Crit. Care Med. 154, 1868-1902.

Xavier, R.F., Ramos, D., Ito, J.T., Rodrigues, F.M., Bertolini, G.N., Macchione, M., et al. (2013). Effects of cigarette smoking intensity on the mucociliary clearance of active smokers. Respiration 86, 479-485. 

Yadav, J., and Kaushik, G. (2014). K Ranga R. Passive smoking affects nasal mucociliary clearance. J. Indian Acad. Clin. Med. 15, 96-99.

Yeates, D.B., Katwala, S.P., Daugird, J., Daza, A.V. and Wong, L.B. (1997). Excitatory and inhibitory neural regulation of tracheal ciliary beat frequency (CBF) activated by ammonia vapour and SO2. Ann. Occup. Hyg. 41, 736-744.