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Event: 1907

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

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. The short name should be less than 80 characters in length. More help
ASL Height, 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

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.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. More help
Organ term
lung

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
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
Oxidative stress [MIE] Leading to Decreased Lung Function [AO] KeyEvent Karsta Luettich (send email) 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
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

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 Low

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 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. 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

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

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). ?

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

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

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.

Evidence for Perturbation by Stressor

Cigarette smoke

Multiple studies showed that exposure of primary human bronchial epithelial cells, either undifferentiated or differentiated at the air-liquid interface, to cigarette smoke decreased ASL height (Hassan et al., 2014; Lambert et al., 2014; Raju et al., 2016; Rasmussen et al., 2014; Schmid et al., 2015). Treatment of immortalized bronchial epithelial 16HBE14o- cells with 10% cigarette smoke extract for 48 hours also resulted in a significant reduction in ASL height (Xu et al., 2015).

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

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.