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Key Event Title
Airway Surface Liquid Height, Decreased
Key Event Components
|epithelial lining fluid||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 Do not cite|
|All life stages||Low|
Key Event Description
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
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
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
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).
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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.
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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.
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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.
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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.