This AOP is licensed under a Creative Commons Attribution 4.0 International License.
Oxidative stress [MIE] Leading to Decreased Lung Function [AO]
Point of Contact
- Karsta Luettich
- Frazer Lowe
- Monita Sharma
- Hasmik Yepiskoposyan
|Author status||OECD status||OECD project||SAAOP status|
|Under development: Not open for comment. Do not cite|
This AOP was last modified on July 23, 2021 06:40
|Cystic Fibrosis Transmembrane Regulator Function, Decreased||July 22, 2021 08:52|
|Airway Surface Liquid Height, Decreased||July 22, 2021 09:02|
|Cilia Beat Frequency, Decreased||July 22, 2021 09:20|
|Mucociliary Clearance, Decreased||July 22, 2021 09:58|
|Decrease, Lung function||April 16, 2021 01:31|
|Mucus Viscosity, Increased||July 23, 2021 04:18|
|FOXJ1 Protein, Decreased||July 23, 2021 07:23|
|Motile Cilia Number/Length, Decreased||July 23, 2021 07:05|
|CFTR Function, Decreased leads to ASL Height, Decreased||July 19, 2021 10:23|
|ASL Height, Decreased leads to CBF, Decreased||July 19, 2021 10:23|
|CBF, Decreased leads to MCC, Decreased||July 19, 2021 10:24|
|MCC, Decreased leads to Decrease, Lung function||July 19, 2021 10:24|
|ASL Height, Decreased leads to Mucus Viscosity, Increased||July 19, 2021 10:39|
|Mucus Viscosity, Increased leads to CBF, Decreased||July 19, 2021 10:40|
|Mucus Viscosity, Increased leads to MCC, Decreased||July 19, 2021 10:41|
|FOXJ1 Protein, Decreased leads to Motile Cilia Number/Length, Decreased||July 23, 2021 06:40|
|Motile Cilia Number/Length, Decreased leads to CBF, Decreased||July 23, 2021 06:40|
This AOP evaluates the major processes known to be involved in regulating efficient mucociliary clearance (MCC). MCC is a key aspect of the innate immune defense against airborne pathogens and inhaled chemicals and is governed by the concerted action of its functional components, the cilia and the airway surface liquid (ASL), which is composed of mucus and periciliary layers (Bustamante-Marin and Ostrowski, 2017). For MCC to be efficient, the depth of the ASL has to be constantly adjusted to allow for efficient cilia beating and mucus transport (Antunes and Cohen, 2007). In healthy subjects, ≥10 mL of airway secretions are continuously produced and transported by the mucociliary escalator daily, and scintigraphy studies showed that MCC is normally accomplished within 24 hours of deposition of radiolabeled aerosols (Rubin, 2002). Disturbances in any of the processes regulating ASL volume, mucus production, mucus viscoelastic properties, or ciliary function can cause MCC dysfunction and are linked to airway diseases such as chronic obstructive pulmonary disease (COPD) or asthma, both of which are characterized by decreased lung function and bear a significant risk of increased morbidity and mortality.
With a surface area of ~100 m2 and ventilated by 10,000 to 20,000 liters of air per day (National Research Council, 1988; Frohlich et al., 2016), the lungs are a major barrier that protect the body from a host of external factors that enter the respiratory system and may cause lung pathologies. Mucociliary clearance (MCC) is a key aspect of the innate immune defense against airborne pathogens and inhaled particles and is governed by the concerted action of its functional components, the cilia and the airway surface liquid (ASL), which comprises mucus and the periciliary layer (Bustamante-Marin and Ostrowski, 2017). In healthy subjects, ≥10 mL airway secretions are continuously produced and transported by the mucociliary escalator daily. Disturbances in any of the processes regulating ASL volume, mucus production, mucus viscoelastic properties, or ciliary function can cause MCC dysfunction and are linked to airway diseases such as chronic obstructive pulmonary disease (COPD) or asthma, both of which bear a significant risk of increased morbidity and mortality. The mechanism by which exposure to inhaled toxicants might lead to mucus hypersecretion and thereby impact pulmonary function has already been mapped in AOP148 on decreased lung function. However, whether an exposure-related decline in lung function is solely related to excessive production of mucus is debatable, particularly in light of the close relationship between mucus, cilia function, and efficient MCC. To date, no single event has been attributed to MCC impairment.
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|Sequence||Type||Event ID||Title||Short name|
|1||KE||1906||Cystic Fibrosis Transmembrane Regulator Function, Decreased||CFTR Function, Decreased|
|2||KE||1907||Airway Surface Liquid Height, Decreased||ASL Height, Decreased|
|3||KE||1908||Cilia Beat Frequency, Decreased||CBF, Decreased|
|4||KE||1909||Mucociliary Clearance, Decreased||MCC, Decreased|
|5||KE||1910||Mucus Viscosity, Increased||Mucus Viscosity, Increased|
|6||KE||1911||FOXJ1 Protein, Decreased||FOXJ1 Protein, Decreased|
|7||KE||1912||Motile Cilia Number/Length, Decreased||Motile Cilia Number/Length, Decreased|
|8||AO||1250||Decrease, Lung function||Decrease, Lung function|
Relationships Between Two Key Events (Including MIEs and AOs)
|CFTR Function, Decreased leads to ASL Height, Decreased||adjacent||High||Moderate|
|ASL Height, Decreased leads to CBF, Decreased||adjacent||Moderate||Moderate|
|CBF, Decreased leads to MCC, Decreased||adjacent||High||Moderate|
|MCC, Decreased leads to Decrease, Lung function||adjacent||Moderate||Moderate|
|ASL Height, Decreased leads to Mucus Viscosity, Increased||adjacent||Moderate||Low|
|Mucus Viscosity, Increased leads to CBF, Decreased||adjacent||Moderate||Moderate|
|Mucus Viscosity, Increased leads to MCC, Decreased||adjacent||High||Moderate|
|FOXJ1 Protein, Decreased leads to Motile Cilia Number/Length, Decreased||adjacent||High||High|
|Motile Cilia Number/Length, Decreased leads to CBF, Decreased||adjacent||High||Moderate|
Life Stage Applicability
Overall Assessment of the AOP
Domain of Applicability
Essentiality of the Key Events
The definition of essentiality implies that the modulation of upstream KEs impacts the downstream KEs in an expected fashion. If blocked or failed to occur, the KEs in the current AOP will not necessarily stop the progression to subsequent KEs. Due to the complex biology of motile cilia formation and function, ASL homeostasis, mucus properties and MCC, the KEs and AO may be triggered because of alternative pathways or biological redundancies. However, when exacerbated, the KEs promote the occurrence of downstream events eventually leading to the AO. The causal pathway starting from the exposure to oxidants and leading to decreased lung function involves parallel routes with KEs, each of which is sufficient to cause the downstream KE to occur. Different mechanisms, such as oxidant-induced decreases in ASL height via CFTR function decline or oxidant-induced decreases in cilia number and length as a result of decreased FOXJ1 levels, lead to decreased CBF and decreased MCC. Each of these pathways contributes to the AO, but their relative contributions are difficult to evaluate. Based on the evidence we judge the key events MIE, KE1, KE3, KE4, KE6 and KE7 as highly essential and suggest moderate essentiality for KE2 and KE5.
Considerations for Potential Applications of the AOP (optional)
Antunes, M.B., and Cohen, N.A. (2007). Mucociliary clearance–a critical upper airway host defense mechanism and methods of assessment. Current opinion in allergy and clinical immunology 7(1), 5-10.
Bustamante-Marin, X.M., and Ostrowski, L.E. (2017a). Cilia and Mucociliary Clearance. Cold Spring Harbor Perspectives in Biology 9(4), a028241. doi: 10.1101/cshperspect.a028241.
Frohlich, E., Mercuri, A., Wu, S., and Salar-Behzadi, S. (2016). Measurements of Deposition, Lung Surface Area and Lung Fluid for Simulation of Inhaled Compounds. Front Pharmacol 7, 181. doi: 10.3389/fphar.2016.00181.
National Research Council (1988). Air Pollution, the Automobile, and Public Health. Washington, DC: The National Academies Press.
Rubin, B.K. (2002). Physiology of airway mucus clearance. Respiratory care 47(7), 761.