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Key Event Title
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Frustrated phagocytosis-induced lung cancer||MolecularInitiatingEvent||Arthur Author (send email)||Under development: Not open for comment. Do not cite||Under Development|
|Frustrated phagocytosis leads to malignant mesothelioma||MolecularInitiatingEvent||Evgeniia Kazymova (send email)||Under development: Not open for comment. Do not cite|
Key Event Description
Phagocytosis is the first line of defence of the organism against foreign matter and therefore is essential for the maintenance of the homeostasis . This process, mainly performed by macrophages, is dividing in two steps, first after recognition and internalization of the foreign matter, the phagosome is formed, and second, this structure is mature in a degradative compartment .
In the lung tissue, macrophages located in the alveolar space are involved in the clearance of foreign matter inhaled. After phagocytosis, cells migrate out of the alveolar space via the mucociliary escalator or the lymphatic system.
High aspect ratio nanoparticles (HARN) are particles with a ratio length – diameter ≥ 3  . Their fibre-shaped, similar to asbestos, is causing concern about their toxicity . HARN include nanotubes, nanorods, nanowires and nanofibers in which carbon nanotubes (CNTs) are the most known and studied. CNT could enter in cells and interact with mitotic spindles as well as nuclei . Macrophages try to phagocytose these particles, however the phagocytosis if incomplete leading to a frustrated phagocytosis. Consequently, the foreign matter is retained in the body because it cannot be cleared by macrophages .
How It Is Measured or Detected
Using in vitro cell models, such as macrophages or epithelial cells, the analysis of interaction between HARN and cells could be performed in time-lapse microscopy  or backscatter electron microscopy .
The frustrated phagocytosis could be measure by different type of microscopy analysis allowing a direct measurement. For examples, time-lapse video microscopy , light microscopy , scanning electron microscopy [6, 9], bright-field microscopy  and backscatter electron microscopy  are used in the literature.
The analysis of phagocytic receptor expression such as MARCO, MSR-1, CD36, TLR4 is an indirect measurement .
The study of the capacity of macrophages to complete phagocytosis process could be performed in vitro using different type of macrophage cell lines (THP-1, NR8383, RAW267) and analysis by microscopy or gene expression or in vivo after exposure of rodents to different type of high aspect ratio nanoparticles and analysis of the remaining quantity of material in the body or the ability of macrophages to phagocyte foreign matter.
Domain of Applicability
The frustrated phagocytosis of high aspect ratio particle can occur in mammals, male or female, and is generally measured in adults.
1. Montano F, Grinstein S, Levin R. Quantitative Phagocytosis Assays in Primary and Cultured Macrophages. 2018;1784:151-63; doi: 10.1007/978-1-4939-7837-3_15.
3. Oberdorster G, Oberdorster E, Oberdorster J. Concepts of nanoparticle dose metric and response metric. 2007;115 6:A290; doi: 10.1289/ehp.115-1892118.
4. Donaldson K, Poland CA. Inhaled nanoparticles and lung cancer - what we can learn from conventional particle toxicology. 2012;142:w13547; doi: 10.4414/smw.2012.13547.
5. Sargent LM, Shvedova AA, Hubbs AF, Salisbury JL, Benkovic SA, Kashon ML, et al. Induction of aneuploidy by single-walled carbon nanotubes. 2009;50 8:708-17; doi: 10.1002/em.20529.
6. 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.
7. 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.
8. Schinwald A, Donaldson K. Use of back-scatter electron signals to visualise cell/nanowires interactions in vitro and in vivo; frustrated phagocytosis of long fibres in macrophages and compartmentalisation in mesothelial cells in vivo. Particle and fibre toxicology. 2012;9:34; doi: 10.1186/1743-8977-9-34.
9. 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.
10. Donaldson K, Murphy FA, Duffin R, Poland CA. Asbestos, carbon nanotubes and the pleural mesothelium: a review of the hypothesis regarding the role of long fibre retention in the parietal pleura, inflammation and mesothelioma. 2010;7:5; doi: 10.1186/1743-8977-7-5.