Hartmut Jaeschke Receives 2019 SOT Translational Impact Award


By Helen Haggerty posted 02-28-2019 15:07


Congratulations to the 2019 Award Recipients

Dr. Hartmut Jaeschke has received the 2019 SOT Translational Impact Award to honor the translational significance of his work in acetaminophen toxicity.

Jaeschke.pngDr. Jaeschke received his PhD in toxicology from the University of Tübingen in Germany in 1983. His extensive career brought him to positions at several institutions, including Baylor College of Medicine, the Upjohn Company, the University of Arkansas, the University of Arizona, and the University of Kansas Medical Center (KUMC), where he presently serves as a professor and chair of the Department of Pharmacology, Toxicology, and Therapeutics.

Dr. Jaeschke’s efforts have resulted in many significant toxicological advancements, and his recent work on translating his acetaminophen hepatotoxicity discoveries in animals to improving human health is of particular note. At KUMC, Dr. Jaeschke established a specialized cell isolation core for human liver cells and performed the first comprehensive study on mechanisms of acetaminophen hepatotoxicity in primary human hepatocytes. Because it confirmed the similarity between mechanisms in human hepatocytes and those that have been found in mice and mouse hepatocytes for the last four decades, this study supported the mouse animal model as a reliable tool for evaluating therapeutic targets for acetaminophen hepatotoxicity and recovery.

Translational Impact Award Lecture.pngAdditionally, Dr. Jaeschke’s work using novel mechanistic biomarkers to gain insight into the human pathophysiology and to predict clinical outcome in acetaminophen overdose patients is being expanded to human acute liver failure caused by other drugs. The major aim of this research is to identify biomarkers that can predict at hospital admission whether an overdose patient will need a liver transplant in order to survive. Finally, in an effort to repurpose existing drugs in the fight against acetaminophen hepatotoxicity, Dr. Jaeschke’s team demonstrated that 4-methylpyrazole is effective against acetaminophen hepatotoxicity in mice and human hepatocytes because it is a potent inhibitor both of cytochrome P450 enzymes and of c-jun N-terminal kinase. Based on these findings, clinical studies have recently been initiated to evaluate the efficacy of 4-methylpyrazole in patients.

Dr. Jaeschke also participates in the field of toxicology outside of his laboratory work. For example, he serves on the editorial boards of many scientific journals and is an associate editor for Toxicological Sciences. More than 400 peer-reviewed publications—a great many of which have been cited more than 100 times—compose Dr. Jaeschke’s prodigious publication history.

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EDITOR'S SIDEBAR: Translational Impact Award Lecture at the SOT 58th Annual Meeting and ToxExpo

Dr. Hartmut Jaeschke will give the Translational Impact Award Lecture on Tuesday, March 12, 2019, from 11:00 am to 12:00 noon, in Room 308 of the Baltimore Convention Center during the SOT 58th Annual Meeting and ToxExpo. The topic of Dr. Jaeschkes lecture is Acetaminophen Hepatotoxicity: Translating Animal Studies to the Human Pathophysiology and the Emergence of New Drug Candidates. The lecture abstract is as follows:

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug. Considered safe at therapeutic levels, it was recognized very early that an overdose can induce severe liver injury and acute liver failure in patients. The first breakthrough came when a mouse model of APAP toxicity was developed, which implicated cytochrome P450-mediated metabolic activation, hepatic GSH depletion, and protein adduct formation as critical events in cell death. This early mechanistic insight led to the introduction of N-acetylcysteine as the first, and still the only, clinically approved antidote against APAP toxicity. More recent studies brought into focus the central role of mitochondria in APAP-induced liver injury. The initial protein adduct formation in mitochondria triggers a mild oxidant stress, which induces the activation of redox-sensitive mitogen activated protein kinases, ultimately leading to phosphorylation of c-jun N-terminal kinase (JNK), which translocates to the mitochondria and amplifies the oxidant stress. These events trigger the mitochondrial membrane permeability transition pore opening with collapse of the membrane potential, mitochondrial matrix swelling with rupture of the outer membrane, and release of endonucleases, which cause nuclear DNA fragmentation. This refined mechanistic understanding of APAP-induced cell death identifies new therapeutic targets including JNK activation and the mitochondrial oxidant stress. Thus, mitochondria-targeted superoxide dismutase mimetics and a combined P450/JNK inhibitor are currently being evaluated in clinical studies as potential new therapeutics for APAP overdose. These examples emphasize the value of clinically relevant animal models for the identification of novel therapeutic targets applicable to patients.