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|
|NM-induced liver inflammation||AdverseOutcome|
Key Event Description
Approximately 29 million people in the European Union suffer from a chronic liver condition . 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) . 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 . 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 . 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 . 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)  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 .
How It Is Measured or Detected
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 .
In mice, neutrophil influx can be analysed using a mouse MPO ELISA kit for lysed tissue .
mRNA expression levels of inflammatory cytokines in tissue samples can be determined by using real-time PCR as described in .
Plasma levels of pro-inflammatory cytokines can be analysed by enzyme linked immunosorbent assay) ELISA using commercial kits .
Domain of Applicability
: human (representative for general application in patients, as liver inflammation is commonly found in patients with DILI)
: rat (nanomaterial-induced)
Regulatory Significance of the Adverse Outcome
- 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
- Larrey D. Epidemiology and individual susceptibility to adverse drug reactions affecting the liver. Semin Liver Dis. 2002;22(2):145-55
- Jaeschke H. Inflammation in response to hepatocellular apoptosis. Hepatology. 2002 Apr;35(4):964-6
- 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
- Arrese M, Cabrera D, Kalergis AM, Feldstein AE. Innate Immunity and Inflammation in NAFLD/NASH. Dig Dis Sci. 2016 May;61(5):1294-303
- 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)
- Huebscher SG. Histological assessment of non-alcoholic fatty liver disease. Histopathol. 2006;49:450–465
- 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
- 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
- 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