Human 3D multicellular microtissues: An upgraded model for the in vitro mechanistic investigation of inflammation-associated drug toxicity

Autor: Jens M. Kelm, S. Messner, T. M. de Kok, Jian Jiang, M.H.M. van Herwijnen, Danyel Jennen, J.C.S. Kleinjans
Přispěvatelé: Experimental in vitro toxicology and dermato-cosmetology, Pharmaceutical and Pharmacological Sciences, Toxicogenomics, RS: GROW - R1 - Prevention, Ondersteunend personeel ODB, CRISP, RS: FSE MaCSBio, RS: FPN MaCSBio, RS: FHML MaCSBio
Rok vydání: 2019
Předmět:
Lipopolysaccharides
0301 basic medicine
INTERLEUKIN-8
Receptors
IgG/genetics
COCULTURE
medicine.medical_treatment
Respiratory chain
Gene Expression Regulation/drug effects
Pharmacology
Toxicology
medicine.disease_cause
HEPATOCYTES
Acetaminophen/toxicity
Tissue Culture Techniques
ACTIVATION
0302 clinical medicine
Analgesics
Non-Narcotic/toxicity
Chemistry
Human primary hepatocytes
Inflammation/metabolism
digestive
oral
and skin physiology
Cytokines/metabolism
General Medicine
Analgesics
Non-Narcotic
3D co-culture
Cytokine
Transcriptome/drug effects
Toxicity
Cytokines
medicine.symptom
Hepatocytes/drug effects
EXPRESSION
KUPFFER CELLS
Inflammation
Kupffer Cells/drug effects
Acetaminophen-inflammation interaction
PHAGOCYTOSIS
03 medical and health sciences
medicine
Humans
Interleukin 8
Human Kupffer cells
Transcriptomics
RECEPTOR
MUTATIONS
Receptors
IgG
Hepatotoxicity
Tissue Culture Techniques/methods
Coculture Techniques
Toll-Like Receptor 4
Lipopolysaccharides/toxicity
030104 developmental biology
Gene Expression Regulation
Hepatic stellate cell
TLR4
Transcriptome
ACETAMINOPHEN
Toll-Like Receptor 4/genetics
030217 neurology & neurosurgery
Oxidative stress
Zdroj: Toxicology Letters, 312, 34-44. Elsevier Ireland Ltd
ISSN: 0378-4274
DOI: 10.1016/j.toxlet.2019.05.004
Popis: Inflammation is one of the factors that may increase the sensitivity of hepatic cells to acetaminophen (APAP) induced toxicity. To investigate the mechanisms, we exposed 3-dimensional (3D) Human Liver Microtissues, a co-culture of primary human hepatocytes (PHH) and Kupffer cells (KCs), to 0, 0.5 (low), 5 (median) and 10 mM (high dose) APAP for 24 h, with/without lipopolysaccharide (LPS). Microarray-technology was used to evaluate the transcriptome changes. In the presence of LPS, the median-dose of APAP is sufficient to inhibit the expression of respiratory chain-and antioxidant-related genes, suggesting the involvement of reactive oxygen species (ROS) and oxidative stress. Furthermore, the median- and high-dose of APAP inhibited the expression of Fc fragment receptor (Fc gamma R)-coding genes, regardless of the presence of LPS. The toll-like receptor 4 (TLR4) expression, however, was continuously elevated after the LPS/APAP co-exposures, which may result in reduced KC-phagocytosis and unbalanced cytokine patterns. Compared to the treatment with LPS only, LPS/APAP co-exposures induced the production of interleukin (IL)-8, a pro-inflammatory cytokine, but suppressed the secretion of IL-6, a cytokine regulating hepatic regeneration, along with the increase in APAP dosages. In addition to the disrupted mitochondrial functions, the presence of LPS exacerbated APAP toxicity. These findings suggest that 3D Microtissues are a suitable model for the mechanistic exploration of inflammation-associated drug toxicity.
Databáze: OpenAIRE
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