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Key Event Title
Mucociliary Clearance, Decreased
Key Event Components
|mucociliary clearance trait||decreased|
Key Event Overview
AOPs Including This Key Event
|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 Do not cite|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 Do not cite|
|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|
|All life stages||High|
Key Event Description
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
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
Evidence for Perturbation by Stressor
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).
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).
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).
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).
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).
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).
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.