Upstream eventFrustrated phagoytosis
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Frustrated phagocytosis-induced lung cancer||adjacent|
Life Stage Applicability
Key Event Relationship Description
Phagocytosis allow the clearance of foreign matter. Incomplete phagocytosis, or frustrated phagocytosis, leads to the persistence of foreign matter. Therefore, in order to clear these substances, phagocytes secretes signals including cytokines for the recruitment of other phagocytes.
Evidence Supporting this KER
The main function of professional phagocytes is to clear the tissue of the foreign matter by phagocytosis . Following exposure to foreign matter, macrophages are activated and therefore secrete pro-inflammatory mediators including cytokines .
In the study of Murphy et al, the human monocytic THP-1 cells treated with carbon nanotubes (CNTs) that induce frustrated phagocytosis showed an increase production of IL-1β, IL-6 and IL-8 whereas treatment by CNTs that did not induce this process did not induce production of these cytokines . Similarly, it was shown that exposure to fibres that induced frustrated phagocytosis of primary human alveolar macrophages is accompanied by induction of IL-6 and IL-8 , and exposure of immortalized MH-S murine alveolar macrophage is accompanied by induction of TNFα and IL-1α [4, 5]. The induction of cytokines was observed in lesser extend after cell treatment with fibres that did not cause frustrated phagocytosis. Indeed, the ratio of the dose-response for TNFα and IL-1α of long fibres to short fibres was about 11 [4, 5].
Uncertainties and Inconsistencies
In very few studies it was analysed the release of cytokines in the same samples as the frustrated phagocytosis.
A study of Zeidler-Erdely et al 2006 showed that human alveolar macrophages are able to engulf fibres with a length of 20 µm and explained this difference with rat alveolar macrophages are smaller than human cells . However, these data are not in accordance with those obtained by Sweeney et al 2015 were they used primary human alveolar macrophages and by Murphy et al 2012 were they used monocytic cells THP-1 differentiated in macrophages [2, 3].
Quantitative Understanding of the Linkage
The length of fibres that induced frustrated phagocytosis accompanied by cytokines production were comprised between 13 and 39.3 µm, whereas fibres with length between 1 and 7 µm were completely phagocytosed and did not induce cytokine production [2, 3, 4].
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
1. Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. 2011;11 11:723-37; doi: 10.1038/nri3073.
2. Murphy FA, Schinwald A, Poland CA, Donaldson K. The mechanism of pleural inflammation by long carbon nanotubes: interaction of long fibres with macrophages stimulates them to amplify pro-inflammatory responses in mesothelial cells. Particle and fibre toxicology. 2012;9:8; doi: 10.1186/1743-8977-9-8.
3. Sweeney S, Grandolfo D, Ruenraroengsak P, Tetley TD. Functional consequences for primary human alveolar macrophages following treatment with long, but not short, multiwalled carbon nanotubes. International journal of nanomedicine. 2015;10:3115-29; doi: 10.2147/IJN.S77867.
4. Padmore T, Stark C, Turkevich LA, Champion JA. Quantitative analysis of the role of fiber length on phagocytosis and inflammatory response by alveolar macrophages. Biochimica et biophysica acta. 2017;1861 2:58-67; doi: 10.1016/j.bbagen.2016.09.031.
5. Ye J, Shi X, Jones W, Rojanasakul Y, Cheng N, Schwegler-Berry D, et al. Critical role of glass fiber length in TNF-alpha production and transcription factor activation in macrophages. 1999;276 3:L426-34; doi: 10.1152/ajplung.1999.276.3.L426.
6. Zeidler-Erdely PC, Calhoun WJ, Ameredes BT, Clark MP, Deye GJ, Baron P, et al. In vitro cytotoxicity of Manville Code 100 glass fibers: effect of fiber length on human alveolar macrophages. 2006;3:5; doi: 10.1186/1743-8977-3-5.