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Relationship: 2959
Title
Interaction with the lung cell membrane leads to Systemic acute phase response
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|---|---|
Substance interaction with lung resident cell membrane components leading to atherosclerosis | non-adjacent | High | Moderate | Ulla Vogel (send email) | Under development: Not open for comment. Do not cite | Under Development |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Male | High |
Female | High |
Life Stage Applicability
Term | Evidence |
---|---|
All life stages | High |
Key Event Relationship Description
This KER presents the association between the interaction of stressors with the lung resident cell membrane components (Key event 1495) and the induction of systematic acute phase response (Key event 1439). The lungs consist of many different cell types. Some of these cell types are capable of detecting danger when in contact with stressors and transmit the signal to initiate the required inflammatory or immunological response (Franks et al., 2008; Hiemstra et al., 2015). Acute phase response is the systemic response to acute and chronic inflammatory states, where acute phase response genes are expressed in organs such as lung and liver, and subsequently secreted into systemic circulation (Gabay & Kushner, 1999). The two major acute phase proteins are C-reactive protein and serum amyloid A (Gabay & Kushner, 1999). The evidence of the KER presented is based on animal studies (mice), controlled human studies and epidemiological studies
Evidence Collection Strategy
KER evidence collection strategy: The evidence for this KER was mainly based on novel experimentation and literature search on the search engine PubMed. The first part of the relationship was considered as the exposure through the respiratory system (inhalation or intratracheal instillation), while the second part of the relationship was assessed measuring the concentration of acute phase proteins in blood plasma or serum from mice and humans.
Evidence Supporting this KER
Biological Plausibility
The biological plausibility is high. Pulmonary inflammation occurs when stressors interact with the airways (Moldoveanu et al., 2009) and acute phase response is induced during inflammatory conditions (Gabay & Kushner, 1999). It has been shown (see table below) that exposure to different stressors produces an increase of acute phase proteins in blood [i.e. C-reactive protein (CRP) and serum amyloid A (SAA)] in humans and mice.
Empirical Evidence
Any substance that is inhaled will interact with a component of the respiratory system, including cells. Any study that shows that inhalation exposure leads to systemic acute phase response is considered evidence for this KER, even if the specific interaction between the substance and the respiratory system has not been investigated.
The table below presents the evidence for this KER. Exposure through the respiratory system (inhalation or intratracheal instillation) of stressors was considered as interaction with lung resident cell membrane components (Key event 1495), while systemic acute phase response is measured as the concentration of acute phase protein in blood plasma or serum (Key event 1439).
Species |
Stressor |
Substance interaction with lung residents cell membrane components |
Systemic acute phase response |
Reference |
Mouse |
Carbon black nanoparticles |
Yes, intratracheal instillation of 162 µg. |
Yes, significant increase of plasma serum amyloid A (SAA) at 1 and day 28 after exposure. |
(Bourdon et al., 2012) |
Mouse |
Multiwalled carbon nanotubes |
Yes, intratracheal instillation of 18, 54 and 128 µg. |
Yes, increased levels of plasma SAA3 after 1 day, with 128 µg. |
(Saber et al., 2013) |
Mouse |
Multiwalled carbon nanotubes (referred as CNTsmall) |
Yes, intratracheal instillation of 18, 54 and 162 µg. |
Yes, increased plasma SAA3 1, 3 and 28 days after exposure to 162 µg, and 3 days after exposure to 18 and 54 µg. |
(Poulsen, Saber, Mortensen, et al., 2015; Poulsen, Saber, Williams, et al., 2015) |
Mouse |
Multiwalled carbon nanotubes (referred as CNTlarge) |
Yes, 18, 54 and 162 µg. intratracheal instillation of |
Yes, increased plasma SAA3 1 and 3 days after exposure to 162 µg, and 3 days after exposure to 54 µg. |
(Poulsen, Saber, Mortensen, et al., 2015; Poulsen, Saber, Williams, et al., 2015) |
Mouse |
Graphene oxide |
Yes, intratracheal instillation of 18, 54 and 162 µg. |
Yes, increased SAA3 plasma levels 3 days after exposure to 54 and 162 µg. |
(Bengtson et al., 2017) |
Mouse |
Multiwalled carbon nanotubes |
Yes, intratracheal instillation of 54 µg. |
Yes, increased SAA1/2 and SAA3 plasma levels 1 day after exposure to. No change in SAA1/2 and SAA3 28 and 92 days after exposure. |
(Poulsen et al., 2017) |
Mouse |
Multiwalled carbon nanotubes |
Yes, intratracheal instillation of 6, 18 and 54 µg. |
Yes, increased SAA1/2 plasma levels 1 day after exposure. No change in SAA1/2 28 and 92 days after exposure. Increased SAA3 plasma levels 1 days after exposure. Increased SAA3 plasma levels 28 and 92 days after exposure. |
(Poulsen et al., 2017) |
Mouse |
Carbon black |
Yes, intratracheal instillation of 162 µg. |
Yes, increased SAA3 plasma levels 1 days after exposure. No change in SAA3 28 and 92 days after exposure. No change in SAA1/2 plasma levels. |
(Poulsen et al., 2017) |
Mouse |
Particulate matter from non-commercial airfield |
Yes, intratracheal instillation of 6, 18 and 54 µg. |
Yes, increased plasma SAA3 levels after exposure to 54 µg. |
(Bendtsen et al., 2019) |
Mouse |
Diesel exhaust particles |
Yes, intratracheal instillation of 18, 54 and 54 µg. |
Yes, increased plasma SAA3 levels after exposure to 54 µg. |
(Bendtsen et al., 2019) |
Mouse |
Nanofibrilated celluloses (FINE NFC, BIOCID FINE NFC and AS) |
Yes, intratracheal instillation of 6 and 18 µg. |
FINE NFC increased plasma SAA3 1 day after exposure to 6 and 18 µg, while AS increased SAA3 after exposure to 18 µg. After 28 days, only 6 µg of FINE NFC increased plasma SAA3. |
(Hadrup, Knudsen, et al., 2019) |
Mouse |
Copper oxide |
Yes, intratracheal instillation of 2, 6 and 12 µg. |
Yes, increased plasma SAA1/2 level after exposure to 6 µg. |
(Gutierrez et al., 2023) |
Mouse |
Tin dioxide |
Yes, intratracheal instillation of 54 and 162 µg. |
Yes, increased plasma SAA3 after exposure to 162 µg. |
(Gutierrez et al., 2023) |
Mouse |
Titanium dioxide |
Yes, intratracheal instillation of 162 µg. |
Yes, increased plasma SAA3 and SAA1/2 after exposure to 162 µg. |
(Gutierrez et al., 2023) |
Mouse |
Carbon black |
Yes, intratracheal instillation of 162 µg. |
Yes, increased plasma SAA3 and SAA1/2 after exposure to 162 µg. |
(Gutierrez et al., 2023) |
Mouse |
Singlewalled carbon nanotubes |
Yes, pharyngeal aspiration of 40 µg. |
Yes, increase serum CRP, haptoglobin and SAP 1 day after exposure. |
(Erdely et al., 2011) |
Mouse |
Multiwalled carbon nanotubes |
Yes, pharyngeal aspiration of 40 µg. |
Yes, increase serum CRP, haptoglobin and SAP 1 day after exposure. No changes after 28 days. |
(Erdely et al., 2011) |
Mouse |
Serum amyloid A |
Yes, intratracheal instillation (2 µg) once a week for 10 weeks. |
Yes, increased levels of endogenous serum SAA3. |
(Christophersen et al., 2021) |
Human |
Welding fumes |
Yes, median exposure to welders (PM2.5) was 1.66 mg/m3 and 0.04 mg/m3 for controls, during 5.3 h. |
No changes in serum C reactive protein (CRP) 6 hours after exposure, but significantly increased serum CRP levels 16 hours after welding. |
(Kim et al., 2005) |
Human |
Wood smoke |
Yes, 4h exposure to 240-280 µg/m3. |
Yes, significant increase in blood SAA after exposure, and 3 and 20 h after exposure, no change in CRP. |
(Barregard et al., 2006) |
Human |
Brazing fumes |
Yes, 6h exposure to 1.4, 2 and 2.5 mg/m3. |
Yes, increased blood CRP 24h after exposure to 2 and 2.5 mg/m3. |
(Brand et al., 2014) |
Human |
Fumes from welding aluminium |
Yes, 6h exposure to 2.5 mg/m3. |
Yes, significantly increased blood CRP 24 after exposure. No change after exposure nor a week after exposure. |
(Hartmann et al., 2014) |
Human |
Fumes from welding zinc coated materials |
Yes, 6h exposure to 2.5 mg/m3. |
Yes, significantly increased blood CRP 24 after exposure. No change after exposure nor a week after exposure. |
(Hartmann et al., 2014) |
Human |
Traffic related particulate matter |
Yes, exposure during work hours. |
Yes, serum CRP and SAA were significantly and positively associated with increases in exposure. |
(Meier et al., 2014) |
Human |
Fumes from brazing galvanized steel, using aluminum bronze wire |
Yes, 6h exposure to 2.5 mg/m3. |
Yes, significant increase in serum CRP and SAA 29 h after exposure. No change 6 nor 10 h after exposure. |
(Baumann et al., 2016) |
Human |
Fumes from welding galvanized steel and aluminum, using zinc wire |
Yes, 6h exposure to 2 mg/m3. |
Yes, significant increase in serum CRP and SAA 29 h after exposure. No change 6 nor 10 h after exposure. |
(Baumann et al., 2016) |
Human |
Fumes from brazing galvanized steel using zinc wire |
Yes, 6h exposure to 2 mg/m3. |
Yes, significant increase in serum CRP 29 h after exposure. No change 6 nor 10 h after exposure. |
(Baumann et al., 2016) |
Human |
Dust from pulp and paper mill |
Yes, exposure during working hours. |
Yes, blood CRP, SAA and fibrinogen were significantly and positively associated with the exposure. |
(Westberg et al., 2016) |
Human |
Zinc welding fumes |
Yes, 6h exposure to 2.5 mg/m3 |
Yes, significant plasma SAA increase at 24 h. No effect at 6h. |
(Baumann et al., 2018) |
Human |
Copper welding fumes |
Yes, 6h exposure to 2.5 mg/m3 |
Yes, significant plasma SAA increase at 24 h. No effect at 6h. |
(Baumann et al., 2018) |
Human |
Zinc and copper welding fumes |
Yes, 6h exposure to 2.5 mg/m3 |
Yes, significant plasma SAA increase at 24 h. No effect at 6h. |
(Baumann et al., 2018) |
Additional empirical evidence can be found in the following links: Additional evidence KER 2959_1 and Additional evidence KER 2959_2.
Uncertainties and Inconsistencies
In the case of nanomaterials, it has been shown that physicochemical characteristics as size, surface area, surface functionalization, shape, composition, among others, affect the magnitude and duration of acute phase response in mice (Bengtson et al., 2017; Gutierrez et al., 2023; Poulsen et al., 2017).
It has been observed that in most controlled human studies, an increase in CRP and/or SAA was observed after exposure to particulate matter (Baumann et al., 2018; Monse et al., 2018, 2021; Walker et al., 2022; Wyatt et al., 2020). However, in other human studies the exposure did not induce acute phase response (Andersen, Saber, Clausen, et al., 2018; Andersen, Saber, Pedersen, et al., 2018), maybe due to a low level of exposure (Andersen et al., 2019).
The table below presents inconsistencies for this KER, where substance interaction with lung resident cell membrane components has occurred, while systemic acute phase response was not observed. Exposure through the respiratory system (inhalation or intratracheal instillation) of stressors was considered as interaction with lung resident cell membrane components, while systemic acute phase response is measured as the concentration of acute phase protein in blood plasma or serum.
Species |
Stressor |
Substance interaction with lung residents cell membrane components |
Systemic acute phase response |
Reference |
Mouse |
Diesel exhaust particles |
Yes, inhalation of 20 mg/m3 for 90 min, in 4 consecutive days. |
No effect. |
(Saber et al., 2009, 2013) |
Mouse |
Carbon black |
Yes, inhalation of 20 mg/m3 for 90 min, in 4 consecutive days. |
No effect. |
(Saber et al., 2009, 2013) |
Mouse |
Reduced graphene oxide |
Yes, intratracheal instillation of 18, 54 and 162 µg. |
No, no change in SAA3 plasma concentration 3 days after exposure. |
(Bengtson et al., 2017) |
Mouse |
Crocidolite |
Yes, intratracheal instillation of 6 and 18 µg. |
No change in SAA1/2 nor SAA3 plasma levels. |
(Poulsen et al., 2017) |
Mouse |
Particulate matter from commercial airport |
Yes, intratracheal instillation of 6, 18 and 54 µg. |
No change in plasma SAA3. |
(Bendtsen et al., 2019) |
Mouse |
Carbon black |
Yes, intratracheal instillation of 54 µg. |
No change in plasma SAA3. |
(Bendtsen et al., 2019) |
Mouse |
Uncoated zinc oxide nanoparticles |
Yes, intratracheal instillation of 0.2, 0.7 and 2 µg. |
No effect on plasma SAA3. |
(Hadrup, Rahmani, et al., 2019) |
Mouse |
Coated zinc oxide nanoparticles |
Yes, intratracheal instillation of 0.2, 0.7 and 2 µg. |
No effect on plasma SAA3. |
(Hadrup, Rahmani, et al., 2019) |
Mouse |
Zinc oxide |
Yes, intratracheal instillation of 0.7 and 2 µg. |
No change in plasma SAA3 or SAA1/2 levels. |
(Gutierrez et al., 2023) |
Mouse |
Aluminum oxide |
Yes, intratracheal instillation of 18 and 54 µg. |
No change in plasma SAA3 or SAA1/2 levels. |
(Gutierrez et al., 2023) |
Human |
Particulate matter and gas from fire extinguishing exercise |
Yes, exposure during training exercises. |
No change was observed on blood CRP or SAA levels. |
(Andersen, Saber, Clausen, et al., 2018) |
Human |
Gas and particulate matter from firefighting activities |
Yes, exposure during firefighting. |
No change was observed on blood CRP or SAA levels. |
(Andersen, Saber, Pedersen, et al., 2018) |
Human |
Diesel exhaust |
Yes, 6h per day for 3 days. |
No change was observed on blood CRP or SAA levels. |
(Andersen et al., 2019) |
Known modulating factors
Quantitative Understanding of the Linkage
Response-response Relationship
The interaction of insoluble nanomaterials with the lungs (Key event 1495) (measured in dosed surface area: dosed mass multiply by specific surface area) is correlated to serum amyloid A (SAA)3 and SAA1/2 plasma levels (Key event 1439) and the responses show a linear regression, in female C57BL/6J mice 1 day after intratracheal instillation (Gutierrez et al., 2023) (Figure 1 and Figure 2).
The Pearson’s correlation coefficient was 0.92 (p <0.001) between log-transformed dosed surface area (dosed mass multiply by specific surface area) and log-transformed SAA3 plasma levels (Figure 1). The linear regression formula obtained was Log SAA3 = 0.9459 *Log Dosed surface area – 2.854 (p=0.01). In the case SAA1/2, the correlation coefficient was 0.83 (p<0.05) between log-transformed dosed surface area and log-transformed SAA1/2 plasma levels was, and the linear regression formula was Log SAA1/2 = 0.6368 *Log Dosed surface area +0.09524 (p=0.01) (Figure 2) (Gutierrez et al., 2023).
Figure 1. Correlations between pulmonary dosed surface area and SAA3 protein in plasma, 1 day after exposure to nanomaterials. Reproduced from Gutierrez et al. (2023).
Figure 2. Correlations between pulmonary dosed surface area and SAA1/2 protein in plasma, 1 day after exposure to nanomaterials. Reproduced from Gutierrez et al. (2023).
Time-scale
In mice, increased serum amyloid A (SAA) protein levels are observed 1 and 3 days after most exposures, however increased SAA levels are not frequently observed 28 or 90 days after exposure (Bourdon et al., 2012; Hadrup et al., 2019; Poulsen et al., 2017; Poulsen, Saber, Mortensen, et al., 2015; Poulsen, Saber, Williams, et al., 2015).
In humans, increased SAA and C-reactive protein has been observed 22h and 2 days after exposure to zinc oxide, but not 3 days after exposure (Monse et al., 2021). After exposure to zinc oxide, copper oxide or a mix both, SAA levels were elevated 24h after exposure in humans, but not 6h after exposure (Baumann et al., 2018).
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Systemic acute phase response is measured as elevation of acute phase proteins in humans (mainly C-reactive protein and serum amyloid A), and serum amyloid A in mice has been shown after exposure to several stressors (see Empirical evidence).
References
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