Investigating acetaminophen hepatotoxicity in multi-cellular organotypic liver models
| Autor: | Sophia M. Orbach, Margaret E. Cassin, Marion Ehrich, Padmavathy Rajagopalan |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Programmed cell death Necrosis Kupffer Cells Biology Toxicology Models Biological Collagen Type I 03 medical and health sciences 0302 clinical medicine In vivo medicine Animals Aspartate Aminotransferases Cells Cultured Acetaminophen Liver cell Endothelial Cells Alanine Transaminase Cytochrome P-450 CYP2E1 General Medicine Analgesics Non-Narcotic Glutathione Coculture Techniques Cell biology 030104 developmental biology Perisinusoidal space medicine.anatomical_structure Biochemistry Liver Rats Inbred Lew 030220 oncology & carcinogenesis Hepatocyte Hepatocytes Cytokines Tumor necrosis factor alpha Female medicine.symptom Chemical and Drug Induced Liver Injury medicine.drug |
| Zdroj: | Toxicology in vitro : an international journal published in association with BIBRA. 42 |
| ISSN: | 1879-3177 |
| Popis: | In vivo studies clearly demonstrate the participation and subsequent death of non-parenchymal liver cells (NPCs) with corresponding hepatocyte effects. This results in a critical need to investigate how major liver cell types function cohesively during hepatotoxicity. However, virtually no studies replicate these phenomena in vitro. We report the design of multi-cellular three-dimensional (3D) organotypic liver models of primary rat hepatocytes, liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs). LSECs and KCs were separated from hepatocytes by a detachable membrane that emulates the physical and chemical properties of the Space of Disse. Acetaminophen (APAP)-induced changes to cellular function and phenotype were investigated. LSECs exhibited approximately 40% cell death at 20mM APAP. KCs exhibited decreased interleukin-10 and increased tumor necrosis factor-alpha and interferon-gamma secretion. The secretion of these proteins altered hepatocyte function and signaling. Both LSECs and KCs maintained phenotypic markers. At 20mM APAP, the 3D models exhibited aspartate aminotransferase to alanine aminotransferase ratios from 2.1-2.5 and 45% glutathione depletion, corresponding to what is seen in vivo. At 10 and 20mM APAP, the 3D models exhibited cell death, primarily through necrosis. Therefore, the 3D cultures described in this report demonstrate significant potential as realistic models for hepatotoxicity studies. |
| Databáze: | OpenAIRE |
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