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Event: 1907

Key Event Title

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

Airway Surface Liquid Height, 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. More help

ASL Height, Decreased

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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Tissue

Organ 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

Organ term
lung

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
	epithelial lining fluid	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
Ox stress-mediated CFTR/ASL/CBF/MCC impairment	KeyEvent	Arthur Author (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	Low	NCBI
Sus scrofa	Sus scrofa	Low	NCBI
Ovis aries	Ovis aries	Low	NCBI
Cavia porcellus	Cavia porcellus	Low	NCBI
Bos taurus	Bos taurus	Low	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
All life stages	Low

Sex Applicability

An indication of the the relevant sex for this KE. More help

Term	Evidence
Mixed	Low

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

The airway surface liquid (ASL) is a liquid layer on the apical side of the respiratory epithelium, reportedly between 5 to 100 μm in depth (Widdicombe and Widdicombe, 1995), and consists of an inner aqueous periciliary liquid layer (PCL) that spans the length of cilia and the outer gel-like mucus layer. The PCL has a low viscosity and enables cilia beating, thereby facilitating the forward movement of the outer mucus layer toward the glottis and, ultimately, its removal by cough or ingestion (Antunes and Cohen, 2007). Both ASL composition and height are considered critical for its function (Fischer and Widdicombe, 2006). Under physiological conditions, ASL composition and height are regulated via vectorial transport of electrolytes, driven by transepithelial transport and apical secretion of Cl⁻ by (predominantly) CFTR, resulting in passive H₂O secretion and, consequently, increased ASL height. Absorption of Na⁺ at the apical side by the epithelial sodium channel ENaC and ENaC’s interaction with the basolateral Na⁺/K⁺-ATPase exchanging Na⁺ for K⁺ leads to net absorption of Na⁺, which in turn drives fluid absorption and therefore decreases ASL height (Althaus, 2013; Hollenhorst et al., 2011). Impairment of CFTR or ENaC function can lead to the dysfunction of the other ion channel (increased CFTR activity leads to decreased ENaC activity and vice versa) (Boucher R., 2003; Boucher, 2004; Schmid et al., 2011), resulting in permanently perturbed ASL height.

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 protocol for the determination of ASL height. In several experimental in vitro studies, confocal fluorescence microscopy scanning in the vertical plane (i.e., in XZ mode) was used to measure ASL height in human and mouse 3D organotypic airway epithelial models, and changes in ASL height could be calibrated using a fluorophore-dextran conjugate to estimate changes in ASL volume (Garcia-Caballero et al., 2009; Lazarowski et al., 2004; Matsui et al., 1998; Roomans et al., 2004; Saint-Criq et al., 2013; Tarran and Boucher, 2002; Tarran et al., 2005; Tarran et al., 2001; Tarran et al., 2006; Zhang et al., 2013). A similar approach was taken for the measurement of ASL height in freshly excised human trachea and bronchi, excised pig tracheas and mouse tracheas in vivo (Jayaraman et al., 2001; Song et al., 2009). A detailed protocol is provided by (Tarran and Boucher, 2002). In addition, ASL height was measured using micro-optical coherence tomography in differentiated human bronchial epithelial cells (Raju et al., 2016), synchrotron phase contrast x-ray imaging in excised mouse tracheas (Morgan et al., 2013; Siu et al., 2008) and live mice (Donnelley et al., 2014), and low-temperature scanning electron microscopy in excised, rapidly frozen specimens of bovine tracheal epithelium (Wu et al., 1996; Wu et al., 1998) and guinea pig lungs (Yager et al., 1994). Furthermore, a specifically designed chamber allowed for evaluation of ASL height in excised guinea pig and sheep tracheas using videomicroscopy under a cold light source or strobe lights (Seybold et al., 1990; Shephard and Rahmoune, 1994), whereas a microelectrode technique was employed to determine ASL height in live guinea pigs (Rahmoune and Shephard, 1995).

Domain of Applicability

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

To date, ASL has been investigated in several species including mice, rats, guinea pigs, ferrets, cats, dogs, cows, monkeys, and humans. Although most studies provide data on its composition rather than its height, it is reasonable to assume that regulation of ASL height is equally critical to MCC across these species.

There are no data related to ASL regulation and homeostasis relative to organismal health, but it is reasonable to assume that decreased ASL, through its impact on MCC, can affect all life stages.

There are no gender-specific data on the regulation of ASL height to our knowledge, but it is reasonable to assume that there is no gender difference.

References

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

Althaus, M. (2013). ENaC inhibitors and airway re-hydration in cystic fibrosis: state of the art. Curr. Mol. Pharmacol. 6, 3-12.

Antunes, M.B. and Cohen, N.A. (2007). Mucociliary clearance–a critical upper airway host defense mechanism and methods of assessment. Curr. Opin. Allergy Clin. Immunol. 7, 5-10.

Boucher, R. (2003). Regulation of airway surface liquid volume by human airway epithelia. Pflügers Arch. 445, 495-498.

Boucher, R.C. (2004). New concepts of the pathogenesis of cystic fibrosis lung disease. Eur. Respir. J. 23, 146-158.

Donnelley, M., Morgan, K.S., Siu, K.K.W., Farrow, N.R., Stahr, C.S., Boucher, R.C., et al. (2014). Non-invasive airway health assessment: Synchrotron imaging reveals effects of rehydrating treatments on mucociliary transit in-vivo. Sci. Rep. 4, 3689.

Fischer, H. and Widdicombe, J.H. (2006). Mechanisms of Acid and Base Secretion by the Airway Epithelium. J. Membr. Biol. 211, 139-150.

Garcia-Caballero, A., Rasmussen, J.E., Gaillard, E., Watson, M.J., Olsen, J.C., Donaldson, S.H., et al. (2009). SPLUNC1 regulates airway surface liquid volume by protecting ENaC from proteolytic cleavage. Proc. Natl. Acad. Sci. U.S.A. 106, 11412-11417.

Hassan, F., Xu, X., Nuovo, G., Killilea, D.W., Tyrrell, J., Da Tan, C., et al. (2014). Accumulation of metals in GOLD4 COPD lungs is associated with decreased CFTR levels. Respir. Res. 15, 69.

Hollenhorst, M.I., Richter, K. and Fronius, M. (2011). Ion transport by pulmonary epithelia. BioMed Res. Int. 174306.

Jayaraman, S., Song, Y., Vetrivel, L., Shankar, L. and Verkman, A.S. (2001). Noninvasive in vivo fluorescence measurement of airway-surface liquid depth, salt concentration, and pH. J. Clin. Invest. 107, 317-324.

Lambert, J.A., Raju, S.V., Tang, L.P., Mcnicholas, C.M., Li, Y., Courville, C.A., et al. (2014). Cystic fibrosis transmembrane conductance regulator activation by roflumilast contributes to therapeutic benefit in chronic bronchitis. Am. J. Respir. Cell Mol. Biol. 50, 549-558.

Lazarowski, E.R., Tarran, R., Grubb, B.R., Van Heusden, C.A., Okada, S. and Boucher, R.C. (2004). Nucleotide release provides a mechanism for airway surface liquid homeostasis. J. Biol. Chem. 279:36855-64.

Matsui, H., Grubb, B.R., Tarran, R., Randell, S.H., Gatzy, J.T., Davis, C.W., et al. (1998). Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease. Cell 95, 1005-1015.

Morgan, K.S., Donnelley, M., Paganin, D.M., Fouras, A., Yagi, N., Suzuki, Y., et al. (2013). Measuring Airway Surface Liquid Depth in Ex Vivo Mouse Airways by X-Ray Imaging for the Assessment of Cystic Fibrosis Airway Therapies. PloS ONE 8, e55822.

Rahmoune, H. and Shephard, K.L. (1995). State of airway surface liquid on guinea pig trachea. J. Appl. Physiol. 78, 2020-2024.

Raju, S.V., Lin, V.Y., Liu, L., Mcnicholas, C.M., Karki, S., Sloane, P.A., et al. (2016). The Cftr Potentiator Ivacaftor Augments Mucociliary Clearance Abrogating Cftr Inhibition by Cigarette Smoke. Am. J. Respir. Cell Mol. Biol. 56, 99-108.

Rasmussen, J.E., Sheridan, J.T., Polk, W., Davies, C.M. and Tarran, R. (2014). Cigarette smoke-induced Ca2+ release leads to cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. J. Biol. Chem. 289, 7671-7681.

Roomans, G.M., Kozlova, I., Nilsson, H., Vanthanouvong, V., Button, B. and Tarran, R. (2004). Measurements of airway surface liquid height and mucus transport by fluorescence microscopy, and of ion composition by X-ray microanalysis. J. Cystic Fibr. 3, 135-139.

Schmid, A., Clunes, L.A., Salathe, M., Verdugo, P., Dietl, P., Davis, C.W., et al. (2011). Nucleotide-mediated airway clearance. Purinergic Regulation of Respiratory Diseases. Springer, pp.95-138.

Saint-Criq, V., Kim, S.H., Katzenellenbogen, J.A. and Harvey, B.J. (2013). Non-Genomic Estrogen Regulation of Ion Transport and Airway Surface Liquid Dynamics in Cystic Fibrosis Bronchial Epithelium. PloS ONE 8, e78593.

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.

Seybold, Z.V., Mariassy, A.T., Stroh, D., Kim, C.S., Gazeroglu, H. and Wanner, A. (1990). Mucociliary interaction in vitro: effects of physiological and inflammatory stimuli. J. Appl. Physiol. 68, 1421-1426.

Shephard, K.L. and Rahmoune, H. (1994). Evaporation-induced changes in airway surface liquid on an isolated guinea pig trachea. J. Appl. Physioly. 76, 1156-1165.

Siu, K.K.W., Morgan, K.S., Paganin, D.M., Boucher, R., Uesugi, K., Yagi, N., et al. (2008). Phase contrast X-ray imaging for the non-invasive detection of airway surfaces and lumen characteristics in mouse models of airway disease. Eur. J. Radiol. 68, S22-S26.

Song, Y., Namkung, W., Nielson, D.W., Lee, J.W., Finkbeiner, W.E. and Verkman, A.S. (2009). Airway surface liquid depth measured in ex vivo fragments of pig and human trachea: dependence on Na+ and Cl- channel function. Am. J. Physiol. Lung Cell. Mol. Physiol. 297, L1131-1140.

Tarran, R., Grubb, B.R., Gatzy, J.T., Davis, C.W. and Boucher, R.C. (2001). The relative roles of passive surface forces and active ion transport in the modulation of airway surface liquid volume and composition. J. Gen. Physiol. 118, 223-236.

Tarran, R. and Boucher, R.C. (2002). Thin-film measurements of airway surface liquid volume/composition and mucus transport rates in vitro. Cystic fibrosis methods and protocols. Springer, pp.479-492.

Tarran, R., Button, B., Picher, M., Paradiso, A.M., Ribeiro, C.M., Lazarowski, E.R., et al. (2005). Normal and cystic fibrosis airway surface liquid homeostasis The effects of phasic shear stress and viral infections. J. Biol. Chem. 280, 35751-35759.

Tarran, R., Trout, L., Donaldson, S.H. and Boucher, R.C. (2006). Soluble mediators, not cilia, determine airway surface liquid volume in normal and cystic fibrosis superficial airway epithelia. J. Gen. Physiol. 127, 591-604.

Widdicombe, J. and Widdicombe, J. (1995). Regulation of human airway surface liquid. Respir. Physiol. 99, 3-12.

Wu, D.X.Y., Lee, C., Widdicombe, J. and Bastacky, J. (1996). Ultrastructure of tracheal surface liquid: low‐temperature scanning electron microscopy. Scanning 18, 589-592.

Wu, D.X.-Y., Lee, C.Y.C., Uyekubo, S.N., Choi, H.K., Bastacky, S.J. and Widdicombe, J.H. (1998). Regulation of the depth of surface liquid in bovine trachea. Am. J. Physiol. Lung Cell. Mol. Physiol. 274, L388-L395.

Xu, X., Balsiger, R., Tyrrell, J., Boyaka, P.N., Tarran, R. and Cormet-Boyaka, E., 2015. Cigarette smoke exposure reveals a novel role for the MEK/ERK1/2 MAPK pathway in regulation of CFTR. Biochimica et biophysica acta. 1850(6), 1224-1232.

Yager, D., Cloutier, T., Feldman, H., Bastacky, J., Drazen, J. and Kamm, R., 1994. Airway surface liquid thickness as a function of lung volume in small airways of the guinea pig. Journal of Applied Physiology. 77(5), 2333-2340.

Zhang, S., Blount, A.C., Mcnicholas, C.M., Skinner, D.F., Chestnut, M., Kappes, J.C., et al., 2013. Resveratrol enhances airway surface liquid depth in sinonasal epithelium by increasing cystic fibrosis transmembrane conductance regulator open probability. PloS one. 8(11), e81589.