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Event: 134

Key Event Title

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

Increased, Activation and Recruitment of Hepatic macrophages (Kupffer Cells)

Short name
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Increased, Activation and Recruitment of Hepatic macrophages (Kupffer Cells)
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Biological Context

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Level of Biological Organization
Cellular

Cell 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
Cell term
Kupffer cell

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

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
macrophage activation Kupffer cell increased

Key Event Overview

AOPs Including This Key Event

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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
human Homo sapiens High NCBI
human and other cells in culture human and other cells in culture High NCBI
mouse Mus musculus High NCBI
Rattus norvegicus Rattus norvegicus High NCBI

Life Stages

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Sex Applicability

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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

Kupffer cells (KCs) are a specialized population of macrophages that reside in the liver; they were first described by Carl Wilhelm von Kupffer (1829–1902). [1] KCs constitute 80%-90% of the tissue macrophages in the reticuloendothelial system and account for approximately 15% of the total liver cell population [2] They play an important role in normal physiology and homeostasis as well as participating in the acute and chronic responses of the liver to toxic compounds. Activation of KCs results in the release of an array of inflammatory mediators, growth factors, and reactive oxygen species. This activation appears to modulate acute hepatocyte injury as well as chronic liver responses including hepatic cancer. Understanding the role KCs play in these diverse responses is key to understanding mechanisms of liver injury.[3] Besides the release of inflammatory mediators including cytokines, chemokines, lysosomal and proteolytic enzymes KCs are a main source of TGF-β1 (transforming growth factor-beta 1, the most potent profibrogenic cytokine). In addition latent TGF-β1 can be activated by KC-secreted matrix metalloproteinase 9 (MMP-9). [4] [5] through the release of biologically active substances that promote the pathogenic process. Activated KCs also release ROS like superoxide generated by NOX (NADPH oxidase), thus contributing to oxidative stress. Oxidative stress also activates a variety of transcription factors like NF-κB, PPAR-γ leading to an increased gene expression for the production of growth factors, inflammatory cytokines and chemokines. KCs express TNF-α (Tumor Necrosis Factor-alpha), IL-1 (Interleukin-1) and MCP-1 (monocyte-chemoattractant protein-1), all being mitogens and chemoattractants for hepatic stellate ceells (HSCs) and induce the expression of PDGF receptors on HSCs which enhances cell proliferation. Expressed TNF-α, TRAIL (TNF-related apoptosis-inducing ligand), and FasL (Fas Ligand) are not only pro-inflammatory active but also capable of inducing death receptor-mediated apoptosis in hepatocytes[6] [7][3] Under conditions of oxidative stress macrophages are further activated which leads to a more enhanced inflammatory response that again further activates KCs though cytokines (Interferon gamma (IFNγ), granulocyte macrophage colony-stimulating factor (GM-CSF), TNF-α), bacterial lipopolysaccharides, extracellular matrix proteins, and other chemical mediators. [8] [9] Besides KCs, the resident hepatic macrophages, infiltrating bone marrow-derived macrophages, originating from circulating monocytes are recruited to the injured liver via chemokine signals. KCs appear essential for sensing tissue injury and initiating inflammatory responses, while infiltrating Ly-6C+ monocyte-derived macrophages are linked to chronic inflammation and fibrogenesis. The profibrotic functions of KCs (HSC activation via paracrine mechanisms) during chronic hepatic injury remain functionally relevant, even if the infiltration of additional inflammatory monocytes is blocked via pharmacological inhibition of the chemokine CCL2 [10] [11] KC activation and macrophage recruitment are two separate events and both are necessary for fibrogenesis, but as they occur in parallel, they can be summarised as one KE. Probably there is a threshold of KC activation and release above which liver damage is induced. Pre-treatment with gadolinium chloride (GdCl), which inhibits KC function, reduced both hepatocyte and sinusoidal epithelial cell injury, as well as decreased the numbers of macrophages appearing in hepatic lesions and inhibited TGF-β1 mRNA expression in macrophages. Experimental inhibition of KC function or depletion of KCs appeared to protect against chemical-induced liver injury.[12]

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

Kupffer cell activation can be measured by means of expressed cytokines, e.g. tissue levels of TNF-a [13], IL-6 expression, measured by immunoassays or Elisa (offered by various companies), soluble CD163 [14] [15] or increase in expression of Kupffer cell marker genes such as Lyz, Gzmb, and Il1b, (Genome U34A Array, Affymetrix); [16]

Domain of Applicability

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

Human: [17][18][19] Rat: [5] Mouse: [20]

References

List of the literature that was cited for this KE description. More help
  1. Haubrich, W.S. (2004), Kupffer of Kupffer cells, Gastroenterology, vol. 127, no. 1, p. 16.
  2. Bouwens, L. et al. (1986), Quantitation, tissue distribution and proliferation kinetics of Kupffer cells in normal rat liver, Hepatology, vol. 6, no. 6, pp. 718-722.
  3. 3.0 3.1 Roberts, R.A. et al. (2007), Role of the Kupffer cell in mediating hepatic toxicity and carcinogenesis, Toxicol Sci, vol. 96, no. 1, pp. 2-15.
  4. Winwood, P.J., and M.J. Arthur (1993), Kupffer cells: their activation and role in animal models of liver injury and human liver disease, Semin Liver Dis, vol. 13, no. 1, pp. 50-59.
  5. 5.0 5.1 Luckey, S.W., and D.R. Petersen (2001), Activation of Kupffer cells during the course of carbon tetrachloride-induced liver injury and fibrosis in rats, Exp Mol Pathol, vol. 71, no. 3, pp. 226-240.
  6. Guo, J. and S.L. Friedman (2007), Hepatic Fibrogenesis, Semin Liver Dis, vol. 27, no. 4, pp. 413-426.
  7. Friedman, S.L. (2002), Hepatic Fibrosis-Role of Hepatic Stellate Cell Activation, MedGenMed, vol. 4, no. 3, pp. 27.
  8. Kolios, G., V. Valatas and E. Kouroumalis (2006), Role of Kupffer Cells in the Pathogenesis of Liver Disease, World J.Gastroenterol, vol. 12, no. 46, pp. 7413-7420.
  9. Kershenobich Stalnikowitz, D. and A.B. Weisssbrod (2003), Liver Fibrosis and Inflammation. A Review, Annals of Hepatology, vol. 2, no. 4, pp.159-163.
  10. Baeck, C. et al. (2012), Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury, Gut, vol. 61, no. 3, pp.416–426.
  11. Tacke, F. and H.W. Zimmermann (2014), Macrophage heterogeneity in liver injury and fibrosis, J Hepatol, vol. 60, no. 5, pp. 1090-1096.
  12. Ide, M. et al. (2005), Effects of gadolinium chloride (GdCl(3)) on the appearance of macrophage populations and fibrogenesis in thioacetamide-induced rat hepatic lesions, J. Comp. Path, vol. 133, no. 2-3, pp. 92–102.
  13. Vajdova, K. et al. (2004), Ischemic preconditioning and intermittent clamping improve murine hepatic microcirculation and Kupffer cell function after ischemic injury, Liver Transpl, vol. 10, no. 4, pp. 520–528.
  14. Grønbaek, H. et al. (2012), Soluble CD163, a marker of Kupffer cell activation, is related to portal hypertension in patients with liver cirrhosis, Aliment Pharmacol Ther, vol 36, no. 2, pp. 173-180.
  15. Møller, H.J. (2012), Soluble CD163.Scand J Clin Lab Invest, vol. 72, no. 1, pp. 1-13.
  16. Takahara, T et al. (2006), Gene expression profiles of hepatic cell-type specific marker genes in progression of liver fibrosis, World J Gastroenterol, vol. 12, no. 40, pp. 6473-6499.
  17. Su, G.L. et al. (2002), Activation of human and mouse Kupffer cells by lipopolysaccharide is mediated by CD14, Am J Physiol Gastrointest Liver Physiol, vol. 283, no. 3, pp. G640-645.
  18. Kegel, V. et al. (2015), Subtoxic concentrations of hepatotoxic drugs lead to Kupffer cell activation in a human in vitro liver model: an approach to study DILI, Mediators Inflamm, 2015:640631, http://doi.org/10.1155/2015/640631.
  19. Boltjes, A. et al. (2014), The role of Kupffer cells in hepatitis B and hepatitis C virus infections, J Hepatol, vol. 61, no. 3, pp. 660-671.
  20. Dalton, S.R. et al. (2009), Carbon tetrachloride-induced liver damage in asialoglycoprotein receptor-deficient mice, Biochem Pharmacol, vol. 77, no. 7, pp. 1283-1290.