Abstract
The search for new criteria indicating acute or chronic pathological processes resulting from exposure to toxic agents, testing of drugs for potential hepatotoxicity, and fundamental study of the mechanisms of hepatotoxicity at a molecular level still represents a challenging issue that requires the selection of adequate research models and tools. Microfluidic chips (MFCs) offer a promising in vitro model for express analysis and are easy to implement. However, to obtain comprehensive information, more complex models are needed. A fundamentally new label-free approach for studying liver pathology is fluorescence-lifetime imaging microscopy (FLIM). We obtained FLIM data on both the free and bound forms of NAD(P)H, which is associated with different metabolic pathways. In clinical cases, liver pathology resulting from overdoses is most often as a result of acetaminophen (APAP) or alcohol (ethanol). Therefore, we have studied and compared the metabolic state of hepatocytes in various experimental models of APAP and ethanol hepatotoxicity. We have determined the potential diagnostic criteria including the pathologically altered metabolism of the hepatocytes in the early stages of toxic damage, including pronounced changes in the contribution from the bound form of NAD(P)H. In contrast to the MFCs, the changes in the metabolic state of hepatocytes in the ex vivo models are, to a greater extent, associated with compensatory processes. Thus, MFCs in combination with FLIM can be applied as an effective tool set for the express modeling and diagnosis of hepatotoxicity in clinics.
Highlights
The animal model included acute APAP-induced injury caused by a single intraperitoneal injection of the toxin, whereas chronic alcohol injury was created by systematic oral administration of ethanol for 12 weeks
In the case of the Microfluidic chips (MFCs), isolated hepatocytes were cultured in a chip, where the relevant toxins (APAP and alcohol) were circulated for a predetermined period of time
In the presence of APAP, we showed that conservation of the tissue structure allows a better maintenance of the metabolic state of the hepatocytes and enables compensatory processes to occur, while in the MFC
Summary
High doses of ethanol through alcohol abuse can cause the development of alcoholic liver disease, which can further promote fibrosis, cirrhosis or hepatocellular carcinoma [3]
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