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Relationship: 2451

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Oxidative Stress leads to CBF, Decreased

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Oxidative Stress

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

CBF, Decreased

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

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	adjacent	High	High	Brendan Ferreri-Hanberry (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 Do not cite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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
Homo sapiens	Homo sapiens	High	NCBI
Cavia porcellus	Cavia porcellus		NCBI
Oryctolagus cuniculus	Oryctolagus cuniculus		NCBI
Bos taurus	Bos taurus		NCBI

Sex Applicability

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

Sex	Evidence
Mixed

Life Stage Applicability

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

Term	Evidence
All life stages

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Because the lung interfaces with the external environment, it is frequently exposed to airborne oxidant gases and particulates, and thus prone to oxidant-mediated cellular damage (Ciencewicki et al., 2008). Oxidant stress—through the action of exogenous and endogenous free radicals, such as super oxides, hydroxyl radicals, and hydrogen peroxides—is a common factor in lung inflammation and various respiratory diseases. The presence of redox-sensitive proteins in motile cilia suggests that oxidant stresses may impact ciliary function negatively (Price and Sisson, 2019). Indeed, exposure of human or rodent ciliated airway epithelial cells to hydrogen peroxide, acetaldehyde, ozone or cigarette smoke—all of which are known to cause oxidative stress—decreases CBF in a dose- and time-dependent manner (Bayram et al., 1998; Burman and Martin, 1986; Gosepath et al., 2000; Hastie et al., 1990; Helleday et al., 1995; Kienast et al., 1994; Knorst et al., 1994a; Min et al., 1999; Simet et al., 2010).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Map 2.0

ID	Experimental Design	Species	Upstream Observation	Downstream Observation	Citation (first author, year)	Notes

Evidence Map

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

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

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Several studies show that oxidants decrease CBF which can be reversed by addition of antioxidants, suggesting a direct effect. However, there is evidence suggesting that oxidant-mediated decreases in CBF cannot be prevented by addition of antioxidants. For example, a polycyanin-induced decrease in CBF in human nasal epithelium could be reversed by treatment with isobutylmethylxanthine and forskolin, both of which increase intracellular cAMP, and also by the cAMP analog dibutyryl cAMP, while antioxidants did not seem to have any effect on CBF (Kanthakumar et al., 1993). Like polycyanin, two other P. aeruginosa toxins, 1-hydroxyphenazine (1-HP) and rhamnolipid reduced CBF which was associated with a decrease in intracellular adenosine nucleotides (Kanthakumar et al., 1996).

Inconsistent with several studies, there are studies that suggest that exposure to cigarette smoke does not inhibit CBF. A study involving 56 human subjects (27 non-smokers and 29 smokers) showed no differences in CBF between the 2 groups. However, a decrease in nasal mucociliary clearance was observed in smokers who exhaled smoke through their noses (Stanley et al., 1986).

While several studies have shown age dependence of CBF, there is evidence that suggests otherwise (Agius et al., 1998).

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Modulating Factor (MF)	MF Specification	Effect(s) on the KER	Reference(s)
CFTR genetic dysfunction / cystic fibrosis	Mutations in CFTR gene and decreased CFTR levels lead in reduced Cl^–channel activity and to compromised fluid and electrolyte transport, consequently to reduced airway surface liquid levels, thus hindering coordinated ciliary beating.	Decrease in CFTR protein activity decreases CBF (see also KERs 2440 and 2441).	Van Goor et al., 2009

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Several studies in various species, including humans and rodents, provide evidence in support of this KER. The empirical evidence confirms both a dose- and time-dependence between the upstream KE/MIE and the downstream KE. Our quantitative understanding of this KER is therefore strong.

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Treatment of human nasal ciliated epithelial cells with 0.4 mM xanthine + 100 mU/mL xanthine oxidase—producing 159 ± 4.0 µM/h H₂O₂—decreased CBF by ca. 1 Hz at 1 h and ca. 2.5 Hz (37.4%) at 4 h. Catalase alone (500 U/mL), or in combination with SOD (300 U/mL ) completely protected the cells from oxidant-mediated ciliary dyskinesia (Feldman et al., 1994).

Treatment of human nasal ciliated epithelial cells with 5 mM glucose + 25 mU/mL glucose oxidase— producing 114 ± 7.7 µM/h H₂O₂—decreased CBF by ca. 2 Hz at 1 h and ca. 4 Hz (38%) at 4 h. The decline in CBF was even larger with 57% (approx. 6 Hz) at 4 h when 100 mU/mL glucose oxidase was used (producing 322 ± 11.5 µM/h H₂O₂). Catalase alone (500 U/mL) completely protected the cells from oxidant-mediated ciliary dyskinesia (Feldman et al., 1994).

Treatment of human nasal ciliated epithelial cells with H₂O₂ at concentrations ≥100 µM dose-dependently decreased CBF in human nasal ciliated epithelial cells, with 100 µM causing a 22.4% reduction and the maximal decrease (51.6%) seen with 500 µM H₂O₂ at 4 h. Adding 100 mU/mL MPO to 150 µM H₂O₂ enhanced the H₂O₂-mediated decrease in CBF (control:11.7 ±0.6 Hz; H₂O₂: 8.2 ± 1.1 Hz, 30% decrease; H₂O₂ + MPO: 5.4±0.2 Hz, 53.8% decrease). (Feldman et al., 1994).

Treatment of human nasal ciliated epithelial cells with HOCl at concentrations ≥100 µM dose-dependently decreased CBF in human nasal ciliated epithelial cells, with 100 µM causing a 26.1% reduction and 500 µM causing the maximal decrease (100%) at 4 h (Feldman et al., 1994).

Treatment of human nasal epithelial cells with 0.4 mM xanthine + 100 mU/mL xanthine oxidase decreased CBF by ca. 50% within 2 min. Addition of 300 U/mL SOD abolished this effect (Min et al., 1999).

Treatment of human nasal epithelial cells with 10 mM H₂O₂ decreased CBF to 36.5 ±4.4% of baseline within 5 min, with a maximal decrease in CBF of 100% seen after 10 min, whereas 1 mM H₂O₂ had no effect on CBF. Treatment of human nasal ciliated epithelial cells with 0.8 mM xanthine + 100 mU/mL xanthine oxidase transiently increased CBF by 12.1±1.0% from baseline. When xanthine concentration was increased to 4 and 8 mM, CBF decreased by 26.8±1.7 and 25.6±1.5%, respectively (Yoshitsugu et al., 1995).

Treatment of bovine ciliated bronchial epithelial cells with acetaldehyde, an oxidative stressor, decreased CBF in a dose-dependent manner. Significant slowing of ciliary beating by ca. 50% was observed with concentrations as low as 15-30 µM, and ciliary beating was completely abrogated at concentrations > 250 µM. Ciliary beating also decreased following treatment with 15-30 µM propionaldehyde (40-50% of control), butyraldehyde (35-65% of control), isobutyraldehyde (20-40% of control), and benzaldehyde (80-90% of control) (Sisson et al., 1991).

Exposure of rabbit tracheal explants to formaldehyde dose-dependently decreased CBF. At 66 µg formaldehyde/cm³, CBF decreased from 12.6 to 11.8 Hz; at 33 µg formaldehyde/cm³, CBF decreased from 13.0 to 10.9 Hz (Hastie et al., 1990).

Exposure of guinea pig trachea to SO₂ at concentrations of 2.5-12.5 ppm for 30 min dose-dependently decreased CBF. Exposure to 2.5 ppm SO₂ caused a small, non-significant decrease in mean CBF, and exposure to 5 ppm SO₂ caused a 45% decrease. The greatest decrease (72 %) in mean CBF was recorded after exposure to 12.5 ppm SO₂ (Knorst et al., 1994a).

Exposure of human nasal epithelial cells (cultured in Ringer’s solution) to SO₂ at concentrations of 2.5-12.5 ppm for 30 min dose-dependently decreased CBF. Exposure to 2.5 ppm yielded a 42.8% decrease, whereas exposure to 12.5 ppm yielded a 96.5% decrease in CBF (Kienast et al., 1994).

A 20-min exposure to NO₂, a known air pollutant, at concentrations of 1.5 or 3.5 ppm did not affect CBF in healthy human subjects at 45 min post-exposure (Helleday et al., 1995).

Exposure of human bronchial epithelial cells from healthy volunteers to 10, 50, and 100 µg/mL Diesel exhaust particles (DEP) significantly decreased CBF by 15.9%, 31.0%, and 55.5%, respectively, from baseline after 24 h (Bayram et al., 1998).

A 4-week exposure of human nasal epithelial cells to 100 µg/m³ ozone had no effect on CBF, whereas 5- and 10-times that concentration significantly decreased CBF (-11.1% at 500 µg/m³; -33.3% at 1000 µg/m³) (Gosepath et al., 2000).

Baseline CBF in tracheal rings from C57Bl/6 mice exposed to cigarette smoke (whole body exposure to mainstream and sidestream cigarette smoke via inhalation from 1R1 reference cigarettes, at 150 mg/m³ total particulate matter for 2 h/day, 5 days/week, for up to 1 year) for 1.5 to 3 months was slightly, but not significantly, increased (∼1 Hz). After 6 months of smoke exposure, however, baseline CBF significantly decreased (∼2–3 Hz) (Simet et al., 2010).

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Treatment of human nasal ciliated epithelial cells with 0.4 mM xanthine + 100 mU/mL xanthine oxidase decreased CBF over time, with a noticeable decrease by ca. 1 Hz at 1 h and a maximal decrease of 37.4% reached at 4 h (Feldman et al., 1994).

Treatment of human nasal ciliated epithelial cells with 5 mM glucose + 25 mU/mL glucose oxidase decreased CBF by ca. 2 Hz at 1 h and a maximal decrease of ca. 4 Hz (38%) at 2 h, that did not change until the end of the experiment at 4 h. When 100 mU/mL glucose oxidase was used, CBF decreased by ca. 2 Hz at 1 h, 4 Hz at 2 h, 5.5 Hz at 3 h, reaching a maximum of 57% (approx. 6 Hz) at 4 h (Feldman et al., 1994).

Treatment of human nasal epithelial cells with 0.4 mM xanthine + 100 mU/mL xanthine oxidase decreased CBF maximally by ca. 50% within 2 min, after which it began to increase again, reaching approx. 80% of the baseline value after 30 min (Min et al., 1999).

Treatment of human nasal ciliated epithelial cells with 0.8 mM xanthine + 100 mU/mL xanthine oxidase transiently increased CBF by 12.1±1.0% from baseline within 15 s, after which it rapidly returned to baseline levels (within 30 min). When xanthine concentrations were increased to 4 and 8 mM, CBF decreased by 26.8±1.7 and 25.6±1.5%, respectively (Yoshitsugu et al., 1995).

Treatment of bovine ciliated bronchial epithelial cells with acetaldehyde reduced CBF rapidly, with a significant drop in CBF occurring within 30 s and a maximal decrease by 3 min (Sisson et al., 1991).

Exposure of rabbit tracheal explants to formaldehyde time-dependently decreased CBF: At 66 µg/cm³, CBF decreased from 12.6 to 11.8 Hz immediately upon addition of HCHO to complete cessation of beating by 10 min. At 33 µg/cm³, CBF decreased from 13.0 to 10.9 Hz by 30 min (Hastie et al., 1990).

At 24 h following a 4-h exposure of healthy human subjects to 3.5 ppm NO₂, there was a significant elevation in CBF from 12.4±0.9 Hz (at baseline, pre-exposure) to 13.8±0.8 Hz (Helleday et al., 1995).

Exposure of human bronchial epithelial cells to DEP significantly decreased CBF from 2 h onward after incubation with 50 to 100 µg/mL DEP and from 6 hours onward after incubation with 10 µg/mL DEP (Bayram et al., 1998).

A 4-week exposure of human nasal epithelial cells to ozone significantly reduced CBF, with effects becoming noticeable at the higher concentrations (-7.1% at 500 µg/m³; -10.3% at 1000 µg/m³) after 2 weeks of exposure and a maximal decrease after 4 weeks (-11.1% at 500 µg/m³; -33.3% at 1000 µg/m³) (Gosepath et al., 2000).

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Unknown

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Age-dependent decreases in CBF have been demonstrated in several species (e.g. guinea pigs, mice, and human) (Bailey et al., 2014; Grubb et al., 2016; Ho et al., 2001; Joki and Saano, 1997; Paul et al., 2013).

Female hormones, i.e. progesterone and estrogen, have been shown to have direct effect on CBF, i.e., progesterone reduces CBF, 17β-estradiol and progesterone receptor antagonists counteract progesterone effects, but estradiol alone has also been shown to have no effect on CBF. However, the mechanism by which these hormones modulate CBF is yet to be elucidated (Jain et al., 2012; Jia et al., 2011).