To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:1703
Increased proinflammatory mediators leads to Recruitment of inflammatory cells
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 the lung resident cell membrane components leading to lung fibrosis||adjacent||Moderate||Low||Cataia Ives (send email)||Under development: Not open for comment. Do not cite||EAGMST Under Review|
|Decreased fibrinolysis and activated bradykinin system leading to hyperinflammation||adjacent||Cataia Ives (send email)||Under development: Not open for comment. Do not cite||Under Development|
|Frustrated phagocytosis leads to malignant mesothelioma||adjacent||High||Not Specified||Evgeniia Kazymova (send email)||Under development: Not open for comment. Do not cite|
|Interaction with lung resident cell membrane components leads to lung cancer||adjacent||Moderate||Low||Evgeniia Kazymova (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
Key Event Relationship Description
Pro-inflammatory mediators are the chemical and biological molecules that initiate and regulate inflammatory reactions. They are secreted following inflammation or exposure to an inflammogen. Commonly measured pro-inflammatory mediators include IL-1 family cytokines, IL-4, IL-5, IL-6, TNFa, IFNg. (https://aopwiki.org/events/1496)
Proinflammatory mediator increase is caused when there’s increased inflammation. This can be found in many ways, including bradykinin system activation or hypofibrinolysis (Koller, https://doi.org/10.1161/ATVBAHA.119.313536).With more proinflammatory mediators, this causes increased signaling from proinflammatory cytokines, which promotes leukocyte recruitment, which will differentiate into proinflammatory cells ( (Villenueve et al, https://doi.org/10.1093/toxsci/kfy047)). Increased proinflammatory mediators means this process happens more, which means increase recruitment of inflammatory cells.
Evidence Collection Strategy
Evidence Supporting this KER
The biological plausibility of this KER is high. There are very well established functional relationships between the secreted signalling molecules and the chemotactic effects on pro-inflammatory cells (Harris, 1954; Petri & Sanz 2018).
Increased proinflammatory mediators means more proinflammatory cytokines, chemokines, vasoactive amines, and lipid mediators (Villenueve et al, https://doi.org/10.1093/toxsci/kfy047). Increased Signaling from these Cytokines and Chemokines promote leukocyte recruitment to areas of infection, including monocytes and neutrophil (Leick et al, doi: 10.1007/s00441-014-1809-9). The leukocytes will differentiate into mature proinflammatory cells, in response to mediators they encounter in the local tissue microenvironment (Villenueve et al, https://doi.org/10.1093/toxsci/kfy047). With higher levels of leukocytes from increased proinflammatory mediators, it causes an increase in proinflammatory cells (Libby, https://doi.org/10.1093/cvr/cvv188).
Uncertainties and Inconsistencies
Attenuation or complete abrogation of KE1 (Event 1496) and KE2 (Event 1497) following inflammogenic stimuli is observed in rodents lacking functional IL-1R1 or other cell surface receptors that engage innate immune response upon stimulation. However, following exposure to MWCNTs, it has been shown that absence of IL-1R1 signalling is compensated for eventually and neutrophil influx is observed at a later post-exposure time point (Nikota et al., 2017). In another study, acute neutrophilic inflammation induced by MWCNT was suppressed at 24 hr in mice deficient in IL1R1 signalling; however, these mice showed exacerbated neutrophilic influx and fibrotic response at 28 days post-exposure (Girtsman et al., 2014). The early defence mechanisms involving DAMPs is fundamental for survival, which may necessitate activation of compensatory signalling pathways. As a result, inhibition of a single biological pathway mediated by an individual cell surface receptor may not be sufficient to completely abrogate the lung inflammatory response. Forced suppression of pro-inflammatory and immune responses early after exposure to substances that cannot be effectively cleared from lungs, may enhance the injury and initiate other pathways leading to exacerbated response.
Most of the studies evaluate one dose at different time points or one-time point at different concentrations. Moreover, some studies have demonstrated that a stressor can lead to the recruitment of pro-inflammatory cells, but the presence of pro-inflammatory mediators was not determined (Westphal et al., 2015).
Recruitment of pro-inflammatory cells is a key event that is complicated to replicate in vitro conditions as cell migration is induced by cooperative chemotactic mediators (Gouwy et al., 2015) which are produced and released from different cells. Therefore, more kinetics studies in co-culture techniques are needed to fill this gap.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Activated pro-inflammatory cells secrete pro-inflammatory mediators, and those mediators' goal is to cause signalling and response, which can lead to chronic inflammation (https://aopwiki.org/events/1497). Chronic inflammation means proinflammatory mediators increase and increased recruitment of inflammatory cells acts in a positive feedback loop, which continues a pro-inflammatory environment.
Domain of Applicability
- Alghsham R et al. Zinc oxide nanowires exposure induces a distinct inflammatory response via CCL11-mediated eosinophil recruitment. Frontiers in immunology, 2019, 10: 2604.
- Bourdon J et al. Carbon black nanoparticle instillation induces sustained inflammation and genotoxicity in mouse lung and liver. Particle and Fibre Toxicology, 2012, 9:5.
- Chen, S et al. No involvement of alveolar macrophages in the initiation of carbon nanoparticle induced acute lung inflammation in mice. Particle and Fibre Toxicology, 2016, 13:33, 1-15.
- Crouzier D et al. Carbon nanotubes induce inflammation but decrease the production of reactive oxygen species in lung. Toxicology, 2010, 272: 39.45.
- Driscoll K. Alveolar macrophage cytokine and growth factor production in a rat model of crocidolite-induced pulmonary inflammation and fibrosis, 1995, 46:2, 155-169.
- Girtsman, T., Beamer, C., Wu, N., Buford, M. and Holian, A. (2012). IL-1R signalling is critical for regulation of multi-walled carbon nanotubes-induced acute lung inflammation in C57BL/6 mice. Nanotoxicology, 8(1), pp.17-27.
- Gasse, P., Mary, C., Guenon, I., Noulin, N., Charron, S., Schnyder-Candrian, S., Schnyder, B., Akira, S., Quesniaux, V., Lagente, V., Ryffel, B. and Couillin, I. (2007). IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice. Journal of Clinical Investigation.
- Gouwy, M et al. Serum amyloid A chemoattracts immature dendritic cells and indirectly provokes monocyte chemotaxis by induction of cooperating CC and CXC chemokines. Eur. J. Immunol. 2015. 45:101-112.
- Hadrup N et al. Acute phase response and inflammation following pulmonary exposure to low doses of zinc oxide nanoparticles in mice. Nanotoxicology, 2019, 13(9): 1275-1292.
- Halappanavar S et al. Pulmonary response to surface-coated nanotitanium dioxide particles includes induction of acute phase response genes, inflammatory cascades, and changes in MicroRNAs: A toxicogenomic study. Environmental and molecular mutagenesis, 2011, 52: 425-439.
- Halappanavar, S., Nikota, J., Wu, D., Williams, A., Yauk, C. and Stampfli, M. (2013). IL-1 Receptor Regulates microRNA-135b Expression in a Negative Feedback Mechanism during Cigarette Smoke-Induced Inflammation. The Journal of Immunology, 190(7), pp.3679-3686.
- HARRIS H. (1954). Role of chemotaxis in inflammation. Physiological reviews, 34(3), 529–562.
- Ho C et al. Quantum dot 705, a cadmium-based nanoparticle, induces persistent inflammation and granuloma formation in the mouse lung. Nanotoxicology, 2013, 7(1): 105-115.
- Hornung, V., Bauernfeind, F., Halle, A., Samstad, E., Kono, H., Rock, K., Fitzgerald, K. and Latz, E. (2008). Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nature Immunology, 9(8), pp.847-856.
- Husain M et al. Carbon black nanoparticles induce biphasic gene expression changes associated with inflammatory responses in the lungs of C57BL/6 mice following a single intratracheal instillation. Toxicology and applied pharmacology, 2015, 289: 573-588.
- Jardine L et al. Lipopolysaccharide inhalation recruits monocytes and dendritic cell subsets to the alveolar airspace. Nature communications, 2019, 10, 1999. Https//doi.org/10.1038/s41467.
- Kamata H et al. Carbon black nanoparticles enhance bleomycin-induced lung inflammatory and fibrotic changes in mice. Experimental Biology and Medicine, 2011, 236, 315-324.
- Khatri M et al. Chronic upper airway inflammation and systemic oxidative stress from nanoparticles in photocopier operators: Mechanistic insights. NanoImpact, 2017, 5: 133-145.
- Lee, S et al., Nickel oxide nanoparticles can recruit eosinophils in the lungs of rats by the direct release of intracellular eotaxin. Particle and Fibre Toxicology, 2016, 13:30, 1-11.
- Leick, M. Azcutia, V. Newton, G. Luscinskas, F. Leukocyte Recruitment in Inflammation: Basic Concepts and New Mechanistic Insights Based on New Models and Microscopic Imaging Technologies. Cell Tissue Res. 2014 Mar; 355(3): 647–656. doi: 10.1007/s00441-014-1809-9
- Liao D et al. Persistent pleural lesions and inflammation by pulmonary exposure of multiwalled carbon nanotubes. Chem Res Toxicol, 2018, 31(10): 1025-1031.
- Libby, P. Fanning the flames: inflammation in cardiovascular diseases. Cardiovascular Research, Volume 107, Issue 3, August, 2015. Pages 307–309, https://doi.org/10.1093/cvr/cvv188
- Ma, J et al. Carbon nanotubes stimulate synovial inflammation by inducing systemic pro-inflammatory cytokines. Nanoscale, 2016, 8, 18070-18086.
- Marchini T et al. Acute exposure to air pollution particulate matter aggravates experimental myocardial infarction in mice by potentiating cytokine secretion from lung macrophages. Basic Res Cardiol, 2016, 111:44.
- Morimoto Y et al. Expression of inflammation-related cytokines following intratracheal instillation of nickel oxide nanoparticles. Nanotoxicology, 2010, 4(2): 161-176.
- Nikota, J., Banville, A., Goodwin, L., Wu, D., Williams, A., Yauk, C., Wallin, H., Vogel, U. and Halappanavar, S. (2017). Stat-6 signaling pathway and not Interleukin-1 mediates multi-walled carbon nanotube-induced lung fibrosis in mice: insights from an adverse outcome pathway framework. Particle and Fibre Toxicology, 14(1).
- Patowary, P et al. Innate inflammatory response to acute inhalation exposure of riot control agent oleoresin capsicum in female rats: An interplay between neutrophil mobilization and inflammatory markers. Experimental lung research, 2020, 46:3-4, 81-97.
- Petri, B., Sanz, MJ. Neutrophil chemotaxis. Cell Tissue Res 371, 425–436 (2018).
- Porter, D et al. Time course of pulmonary response of rats to inhalation of crystalline silica: NF-kB activation, inflammation, cytokine production, and damage. Inhalation Toxicology, 2002, 14:349-367, 349-367.
- Porter, D et al. Mouse pulmonary dose-and time course-responses induced by exposure to nitrogen-doped multi-walled carbon nanotubes. Inhalation toxicology, 2020, 32:1, 24-38.
- Poulsen S et al. Transcriptomic analysis reveals novel mechanistic insight into murine biological responses to multi-walled carbon nanotubes in lungs and cultured lung epithelial cells. Plos one, 2013, 8,11, e80452.
- Rabolli, V., Badissi, A., Devosse, R., Uwambayinema, F., Yakoub, Y., Palmai-Pallag, M., Lebrun, A., De Gussem, V., Couillin, I., Ryffel, B., Marbaix, E., Lison, D. and Huaux, F. (2014). The alarmin IL-1α is a master cytokine in acute lung inflammation induced by silica micro- and nanoparticles. Particle and Fibre Toxicology, 11(1).
- Rahman L et al. Toxicogenomics analysis of mouse lung responses following exposure to titanium dioxide nanomaterials reveal their disease potential at high doses. Mutagenesis, 2017, 32, 59-76.
- Rahman L et al. Multi-walled carbon nanotube-induced genotoxic, inflammatory and pro-fibrotic responses in mice: investigating the mechanisms of pulmonary carcinogenesis. Mutat Res Gen Tox En, 2017, 823: 28-44.
- Rider, P., Carmi, Y., Guttman, O., Braiman, A., Cohen, I., Voronov, E., White, M., Dinarello, C. and Apte, R. (2011). IL-1α and IL-1β Recruit Different Myeloid Cells and Promote Different Stages of Sterile Inflammation. The Journal of Immunology, 187(9), pp.4835-4843.
- Riva D et al. Low dose of fine particulate matter (PM2.5) can induce acute oxidative stress, inflammation and pulmonary impairment in healthy mice. Inhalation toxicology, 2011, 23(5): 257-267.
- Saito F et al. Role of interleukin-6 in bleomycin-induced lung inflammatory changes in mice. Am J Respir Cell Mol Biol, 2008, 38, 566-571.
- Schremmer, I et al. Kinetics of chemotaxis; cytokine; and chemokine release of NR8383 macrophages after exposure to inflammatory and inert granular insoluble particles. Toxicology Letters, 2014, http://dx.doi.org/10.1016/j.toxlet.2016.08.2014.
- Shvedova A et al. Unusual inflammatory and fibrogenic pulmonary responses to single-walled carbon nanotubes in mice. Am J Physiol Lung Cell Mol Physiol, 2005, 289: L698-L708.
- Song J et al. Polyhexamethyleneguanidine phosphate induces severe lung inflammation, fibrosis, and thymic atrophy. Food and chemical toxicology, 2014, 69: 267-275.
- Suwara, M., Green, N., Borthwick, L., Mann, J., Mayer-Barber, K., Barron, L., Corris, P., Farrow, S., Wynn, T., Fisher, A. and Mann, D. (2014). IL-1α released from damaged epithelial cells is sufficient and essential to trigger inflammatory responses in human lung fibroblasts. Mucosal Immunology, 7(3), pp.684-693.
- Villeneuve D., Landesmann B., Allavena P., Ashley N., Bal-Price, A., Corsini E., Halappanavar S., Hussell T., Laskin D., Lawrence T., Nikolic-Paterson D., Pallardy M., Paini A., Pieters R., Roth R., Tschudi-Monnet F. Representing the Process of Inflammation as Key Events in Adverse Outcome Pathways. Toxicological Sciences, Volume 163, Issue 2, June 2018, Pages 346–352, https://doi.org/10.1093/toxsci/kfy047
- Wang G et al. Ambient fine particulate matter induce toxicity in lung epithelial-endothelial co-culture models. Toxicol Lett, 2019, 301: 133-145.
- Westphal, GA et al. Particle induced cell migration assay (PICMA): a new in vitro assay for inflammatory particle effects based on permanent cell lines. Toxicol. In vitro, 2015, 29(5):997-1005.