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Relationship: 2441
Title
ASL Height, Decreased leads to CBF, Decreased
Upstream event
Downstream event
AOPs Referencing Relationship
| AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
|---|---|---|---|---|---|---|
| Oxidative stress Leading to Decreased Lung Function via CFTR dysfunction | adjacent | Moderate | Low | Arthur Author (send email) | Open for comment. Do not cite |
Taxonomic Applicability
Sex Applicability
| Sex | Evidence |
|---|---|
| Mixed | Moderate |
Life Stage Applicability
| Term | Evidence |
|---|---|
| All life stages | High |
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. 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 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). Decreased ASL height or ASL dehydration, if not rebalanced, results in cilia collapse and thereby effectively hinders coordinated ciliary beating (Knowles and Boucher, 2002; Matsui et al., 1998; Tarran et al., 2001)
| ID | Experimental Design | Species | Upstream Observation | Downstream Observation | Citation (first author, year) | Notes |
|---|
| Title | First Author | Biological Plausibility |
Dose Concordance |
Temporal Concordance |
Incidence Concordance |
|---|
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
Uncertainties and Inconsistencies
Although the empirical evidence suggests a link between decreased ASL height and reduced cilia beating, causality between the two KEs has not been proven nor has this KER been systematically examined or quantified yet.
Unknown
The evidence provided here stems from studies reporting on the effects of stressors such as cigarette smoke on both ASL height and CBF. Although the empirical evidence suggests a link between decreased ASL height and reduced ciliary beating, causality between the two KEs has not been proven nor has this KER been systematically examined or quantified yet. Our quantitative understanding of this KER is therefore poor (weak).
Response-response Relationship
Osmotic compression of the ASL between 300 and 800 Pa (using large dextran molecules, endogenous mucin or low-melting point agarose) had minimal effects on cilia height or cilia beating. At osmotic pressures exceeding 800 Pa, the ASL became compressed from 7 to less than 2 µm, and cilia height decreased to approx. the same extent (consequently, cilia were not beating at full height) (Button et al., 2012).
Exposure of primary human airway epithelial cells to cigarette smoke (5 min, ca. 12 puffs at 1 puff every 30 seconds) resulted in a ca. 2-fold reduction in ASL height. CBF decreased from 4.19 ± 0.24 Hz (in air control) to 1.28 ± 0.06 Hz. Replenishment of the ASL by addition of 50 µL PBS restored CBF in air- and smoke-exposed cultures (6.04 ± 0.3 Hz vs 6.82 ± 0.37 Hz) (Xu et al., 2015).
Treatment of murine nasal septal epithelia with Sinupret, a phytomedicine, significantly increased ASL depth from 5.25±0.38 to 9.14±0.42 µm and increased the mean CBF from 1.52±0.10 to 2.05±0.15 when applied apically, from 0.99±0.04 to 1.37±0.09 when applied basally, and from 1.53±0.09 to 2.17±0.12 when applied to both compartments (Zhang et al., 2014).
An experimental compound targeting ENaC termed “compound A” dose-dependently increased ASL height in ASL-depleted cultures (absorptive mode analysis). Following exposure to cigarette smoke (1 2R4F cigarette, ISO smoking regimen), ASL decreased by approx. 4 µm within 30 min compared to air controls, and this could be prevented by a 2.5-h pre-treatment with 1 µM compound A. In the same cultures, CBF was significantly decreased by more than 1 Hz following cigarette smoke exposure, whereas pre-treatment with compound A completely prevented this (Åstrand et al., 2014).
Time-scale
ASL height of primary human airway epithelial cells dropped within 30 min of exposure to cigarette smoke (5 min, ca. 12 puffs at 1 puff every 30 s). ASL height stayed at that reduced level up until 70 min post-exposure. Significant decreases in CBF in cigarette smoke-exposed cultures were seen 3 h post-exposure (Xu et al., 2015).
Treatment of primary human bronchial epithelial cells from a cystic fibrosis patient with the G551D/ΔF508 genotype, grown as monolayer at the air-liquid interface, with the CFTR potentiator VX-770 (10 µM) for 72 h increased ASL height by approx. 25%, and treatment for 5 days more than doubled CBF (Van Goor et al., 2009).
Exposure of human bronchial epithelial cells to cigarette smoke decreased ASL height by approx. 4 µm within 30 min, whereas pre-treatment with 1 µM compound A prevented this decrease. When compound A was added 30 min after exposure to cigarette smoke, ASL height returned to normal levels significantly more quickly. In the same exposed cultures CBF was decreased by more than 1 Hz within 1 h (Åstrand et al., 2014).
Known Feedforward/Feedback loops influencing this KER
Unknown