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Event: 902

Key Event Title

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

Inflammation, Liver

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Inflammation, Liver
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Organ

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Organ term
liver

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
liver inflammation occurrence

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
TLR9 activation leading to Multi Organ Failure and ARDS KeyEvent Gillina Bezemer (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
mouse Mus musculus High NCBI
human Homo sapiens High NCBI
rat Rattus norvegicus Moderate NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Sex Applicability

An indication of the the relevant sex for this KE. More help

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Approximately 29 million people in the European Union suffer from a chronic liver condition [1]. Inflammation is a crucial link that is related to many of these conditions, with the potential for the development of cirrhosis or primary liver cancer which represent the end-stage of liver pathology and are often associated with mortality: chronic hepatitis (A-E), non-alcoholic steatohepatitis (NASH) which is the progressive form of non-alcoholic fatty liver disease (NAFLD), primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC) [1]. Drug-induced liver injury (DILI) still is a major problem in drug development as its early detection is problematic, and acute liver inflammation is the most common symptom. DILI is the main cause for withdrawal of drugs from the pharmaceutical market [2]. Liver inflammation is marked by an increased influx of neutrophils, following the secretion of signaling factors such as CXC chemokines and macrophage inflammatory protein 2 (MIP-2) from damaged cells [3]. Kupffer cells (KCs), the resident macrophages of the liver and accounting for about 15-20% of total cell numbers in a healthy liver. They are the gatekeepers in the liver, as they monitor the blood that enters this organ [4][5]. Activation of KCs by activation of toll like receptors, for example, leads to the recruitment of further inflammatory cells as well as amplified KC activation. This, in turn, activates Hepatic stellate cells (HSCs) [5] which can link liver inflammation to further severe outcomes such as development of fibrosis

A list of drugs generally known to induce DILI can be found here [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

Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?

Liver inflammation is usually confirmed by analysis of histological features, marked by influx of inflammatory cells (mainly neutrophils) which can be stained by using Haematoxylin and eosin [7].

In mice, neutrophil influx can be analysed using a mouse MPO ELISA kit for lysed tissue [4].

mRNA expression levels of inflammatory cytokines in tissue samples can be determined by using real-time PCR as described in [8].

Plasma levels of pro-inflammatory cytokines can be analysed by enzyme linked immunosorbent assay) ELISA using commercial kits [9].

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

[7]: human (representative for general application in patients, as liver inflammation is commonly found in patients with DILI)

[8][4][9]: mouse (nanomaterial-induced)

[10]: rat (nanomaterial-induced)

References

List of the literature that was cited for this KE description. More help
  1. 1.0 1.1 Blachier M, Leleu H, Peck-Radosavljevic M, Valla DC, Roudot-Thoraval F. The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol. 2013 Mar;58(3):593-608
  2. Larrey D. Epidemiology and individual susceptibility to adverse drug reactions affecting the liver. Semin Liver Dis. 2002;22(2):145-55
  3. Jaeschke H. Inflammation in response to hepatocellular apoptosis. Hepatology. 2002 Apr;35(4):964-6
  4. 4.0 4.1 4.2 Kermanizadeh A, Brown DM, Hutchison GR, Stone V. Engineered Nanomaterial Impact in the Liver following Exposure via an Intravenous Route–The Role of Polymorphonuclear Leukocytes and Gene Expression in the Organ. Journal of Nanomed & Nanotechnol 2012;04(01):1–7
  5. 5.0 5.1 Arrese M, Cabrera D, Kalergis AM, Feldstein AE. Innate Immunity and Inflammation in NAFLD/NASH. Dig Dis Sci. 2016 May;61(5):1294-303
  6. Ortega-Alonso A, Stephens C, Lucena MI, Andrade RJ. Case Characterization, Clinical Features and Risk Factors in Drug-Induced Liver Injury. Int J Mol Sci. 2016 May 12;17(5)
  7. 7.0 7.1 Huebscher SG. Histological assessment of non-alcoholic fatty liver disease. Histopathol. 2006;49:450–465
  8. 8.0 8.1 Cui Y, Liu H, Zhou M, Duan Y, Li N, Gong X, Hu R, Hong M, Hong F. Signaling pathway of inflammatory responses in the mouse liver caused by TiO2 nanoparticles. 2011; J. Biomed. Mater. Res. - Part A 96 A:221–229
  9. 9.0 9.1 Ma L, Zhao J, Wang J, Liu J, Duan Y, Liu H, Li N, Yan J, Ruan J, Wang H, Hong F. The Acute Liver Injury in Mice Caused by Nano-Anatase TiO2. Nanoscale Res Lett. 2009 Aug 1;4(11):1275-85
  10. Alarifi S, Ali ., Al-Doaiss AA, Ali BA, Ahmed M, Al-Khedhairy AA. Histologic and apoptotic changes induced by titanium dioxide nanoparticles in the livers of rats. Intern J Nanomed. 2013;8:3937–3943