Key Event Overview
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AOPs Including This Key Event
|AOP Name||Event Type||Essentiality|
|Lysosomal damage leading to liver inflammation||KE||Strong|
Level of Biological Organization
How this Key Event works
TNF-induced cytokines and chemokines, such as IL-6, IL-8, GMCSF, CXCL1, and RANTES, can instigate and amplify immune responses through triggering the production of acute phase proteins and the recruitment of neutrophils, macrophages, and basophils to the site of inflammation, and by triggering increased production of monocytes/macrophages from bone marrow. Monocytes are the precursors of macrophages and dendritic cells and circulate in the blood for 1-3 days. Upon secretion of chemokines such as CCL2 which is also referred to as monocyte chemoattractant protein 1 (MCP1), they can migrate towards affected tissue. This was nicely demonstrated when depletion of MCP-1 in supernatants of Fas-stimulated cells was sufficient to block almost all THP-1 monocyte chemotaxis. Using an in vivo mouse model, the authors found that Fas stimulation could trigger phagocyte migration by administration of anti-Fas (Jo2) antibody into C57BL/6 mice within 10 h of anti-Fas administration. This correlated with extensive cell death in the thymus and a dramatic increase of CD11b-positive macrophages in the same tissue.
Neutrophils, on the other hand, account for about 50 70 % of all blood leukocytes in the human body . Upon an inflammatory event, neutrophil production is upregulated, and its lifetime increases as a response to platelet activating factor (PAF), granulocyte-colony stimulating factor (G-CSF) or various pro-inflammatory cytokines, such as interleukin 1ß (IL-1ß) . The crucial role of PMN in the human immune system is long known. In 1968, Baehner and Karnovsky described a link between a reduced PMN activity and the development of chronic granulomatous disease (CGD) . The important peroxidase-mediated bactericidal role of PMN and the formation of superoxide radicals as one of the main bactericial mechanisms was already described more than 30 years ago . A strong negative correlation between the chemotactic ability of PMN and patients with increased bacterial sepsis was demonstrated , and clinical morbidity from infections is clearly increased with a reduced number of circulating PMN in the blood . The neutrophilic cytosol contains granules that are filled with a variety of proteins, such as defensins, bactericidal-permeability-increasing protein, proteases (e.g. elastase, cathepsins), and myeloperoxidase (MPO) that consumes hydrogen peroxide (H2O2) and generates hypochlorous acid (HOCl), the most bactericidal oxidant that is produced by PMN . Activated neutrophils are capable of producing a variety of pro-inflammatory cytokines, e.g. IL-1ß, IL-6, IL-12 and IL-23, and transport internalised pathogens to lymph nodes to support macrophages and dendritic cells in antigen presentation. Also, contact with pathogens results not only in phagocytosis, but also in the so-called oxidative burst, marked by an increased consumption of molecular oxygen and resulting production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) .
Deregulation of this response by constant stimulation of PMNs, as could be shown for nanoparticles for example, ultimately leads to the establishment of a (chronic) inflammation. Here, also macrophages play a vital role. Resident alveolar macrophages, such as Kupffer cells in the liver, that usually phagocyte microorgansims or particles will be activated when overwhelmed by the amount of invading pathogens and in turn release inflammatory cytokines and chemokines. Consequently, neutrophils are recruited and activated as described above .
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?
Chemotaxis assays can be performed in vitro/ex vivo by using Chemotaxis Chambers (for example Neuro Probe Chambers). Supernatants can be added to the bottom well of the chamber and 3–8 mm nitrocellulose filters are placed on top, while the top chamber contains the inflammatory cells (for example neutrophils). After a certain time period, the number of migrated cells towards the lower chamber can be determined by staining of the cells.
Influx of inflammatory cells (mainly neutrophils) can be analysed by tissue staining by using Haematoxylin and eosin .
In mice, neutrophil influx can be analysed using a mouse MPO ELISA kit for lysed tissue .
Evidence Supporting Taxonomic Applicability
- Cullen SP, Henry CM, Kearney CJ, Logue SE, Feoktistova M, Tynan GA, Lavelle EC, Leverkus M, Martin SJ. Fas/CD95-induced chemokines can serve as "find-me" signals for apoptotic cells. Mol Cell. 2013 Mar 28;49(6):1034-48
- Freitas M, Lima JL, Fernandes E. Optical probes for detection and quantification of neutrophils' oxidative burst. A review. Anal Chim Acta 2009;649(1):8-23
- Wessels I, Jansen J, Rink L, Uciechowski P. Immunosenescence of polymorphonuclear neutrophils. ScientificWorldJournal 2010;10:145-60
- Baehner RL, Karnovsky ML. Deficiency of reduced nicotinamide-adenine dinucleotide oxidase in chronic granulomatous disease. Science 1968;162(859):1277-9
- Klebanoff SJ. Iodination of bacteria: a bactericidal mechanism. J Exp Med 1967;126(6):1063-78
- Klebanoff SJ, Rosen H. The role of myeloperoxidase in the microbicidal activity of polymorphonuclear leukocytes. Ciba Found Symp 1978;(65):263-84
- Christou NV, Meakins JL. Neutrophil function in surgical patients: Two inhibitors of granulocyte chemotaxis associated with sepsis. J Surg Res 1979;26(4):355-364
- Nauseef WM. How human neutrophils kill and degrade microbes: an integrated view. Immunol Rev 2007;219:88-102
- Silva MT. Neutrophils and macrophages work in concert as inducers and effectors of adaptive immunity against extracellular and intracellular microbial pathogens. J Leukoc Biol 2010;87(5):805-13
- Babior BM. Phagocytes and oxidative stress. Am J Med 2000;109(1):33-44
- Driscoll KE, Deyo LC, Carter JM, Howard BW, Hassenbein DG, Bertram TA. Effects of particle exposure and particle-elicited inflammatory cells on mutation in rat alveolar epithelial cells. Carcinogenesis 1997;18(2):423-30
- Knaapen AM, Seiler F, Schilderman PA, Nehls P, Bruch J, Schins RP, Borm PJ. Neutrophils cause oxidative DNA damage in alveolar epithelial cells. Free Radic Biol Med 1999;27(1-2):234-40
- Huebscher SG. Histological assessment of non-alcoholic fatty liver disease. Histopathol. 2006;49:450–465
- 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
- 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