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Event: 1668

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Frustrated phagocytosis

Short name

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Biological Context

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Level of Biological Organization
Cellular

Cell term

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Organ term

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
phagocytosis	macrophage	decreased

Key Event Overview

AOPs Including This Key Event

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AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Frustrated phagocytosis-induced lung cancer	MolecularInitiatingEvent	Carole Seidel (send email)	Under development: Not open for comment. Do not cite	Under Development
Frustrated phagocytosis leads to malignant mesothelioma	MolecularInitiatingEvent	Penny Nymark (send email)	Under development: Not 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 Do not cite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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
mammals	mammals		NCBI

Life Stages

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Life stage	Evidence
Adult

Sex Applicability

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Term	Evidence
Unspecific

Key Event Description

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Phagocytosis is the first line of defence of the organism against foreign matter and therefore is essential for the maintenance of the homeostasis [1]. 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 [1].

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 [2] [3]. Their fibre-shaped, similar to asbestos, is causing concern about their toxicity [4]. 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 [5]. 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 [6].

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

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 [7] or backscatter electron microscopy [8].

The frustrated phagocytosis could be measure by different type of microscopy analysis allowing a direct measurement. For examples, time-lapse video microscopy [7], light microscopy [9], scanning electron microscopy [6, 9], bright-field microscopy [8] and backscatter electron microscopy [8] are used in the literature.

The analysis of phagocytic receptor expression such as MARCO, MSR-1, CD36, TLR4 is an indirect measurement [6].

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

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The frustrated phagocytosis of high aspect ratio particle can occur in mammals, male or female, and is generally measured in adults.

References

List of the literature that was cited for this KE description. More help

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.

2. safenano.org.

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.