Drug-induced organ toxicity is a major concern for pharmaceutical industry, due to removal of a high number of drugs from the market, as well as for public health, due to numerous hospitalizations... Show moreDrug-induced organ toxicity is a major concern for pharmaceutical industry, due to removal of a high number of drugs from the market, as well as for public health, due to numerous hospitalizations and patient death. The organs that are the primary target for such toxicities are the liver and the kidneys since both organs are continuously exposed to high concentrations of drugs and have high metabolic capacities. The immune system has been shown to be involved in the toxicity of several drugs- inducing liver and kidney injury. In particular, the cytokine tumor necrosis factor _ (TNF-_) has been shown to be the main constituent of the inflammatory processes responsible for the aggravation of drug-induced liver and kidney injuries. In this thesis, the role of TNF-_ in drug-induced organ injury was investigated. The main question was to assess the possible synergy between TNF-_ and druginduced cytotoxicities, and to unravel the underlying molecular mechanisms of such a synergy. Show less
Adverse drug reactions are problematic for both society and pharmaceutical industry. The costs are high in severe cases: for pharmaceutical companies due to the loss of income if a drug needs to be... Show moreAdverse drug reactions are problematic for both society and pharmaceutical industry. The costs are high in severe cases: for pharmaceutical companies due to the loss of income if a drug needs to be removed from the market; for society due to the extra healthcare that is required to treat the affected individuals. Liver damage upon drug intake is the most common type of adverse drug reaction and reason for drug withdrawal. What makes the liver such a vulnerable target is its role as the main drug-metabolizing organ and its large amount of stationary immune cells. This results in frequent exposure to drug metabolite-induced and inflammatory stress. In this thesis I have investigated the role of the signaling induced by the pro-inflammatory cytokine TNF_ in the exacerbation of drug-induced liver injury using an in vitro liver cell model. Using this model and methods such as high content imaging, gene array analysis and functional genomics we have gotten closer to understanding the molecular mechanisms of liver injury. This knowledge can be used to design novel tests for the drug-industry to assess the toxicity of novel drug candidates as well as to pin-point potentially susceptible individuals. Show less
