Hartmut Jaeschke, PhD
University Distinguished Professor & Chair
Ph.D., University of Tübingen, Germany, 1983
Mechanisms of inflammatory liver injury and drug-induced hepatotoxicity; signaling mechanisms of apoptotic and necrotic cell death in liver cells.
Acetaminophen (APAP) overdose is a significant clinical problem and is the chief cause of acute liver failure in the U.S. Our lab uses multiple models to develop a better understanding of the mechanisms of APAP-induced liver injury. In particular, we study the roles played by covalent protein binding (particularly mitochondrial protein binding), mitochondrial dysfunction, oxidative stress, and kinase activation and other cell signaling pathways involved in programmed necrosis of hepatocytes (Figure 1). In addition, we are investigating adaptive mechanisms such as autophagy (in collaboration with Dr. Ding's laboratory) and mitochondrial biogenesis and their role in cell death and regeneration. Going beyond the rodent model, we are engaged in multiple collaborations with clinicians on both the local and national levels to translate the mechanistic insights gained from these studies to humans. To do this, we are investigating mechanisms of APAP-induced cell death in primary human hepatocytes and in metabolically competent human hepatoma cells (HepaRG cells). In addition we are developing novel mechanistic biomarkers that can be measured in serum of APAP overdose patients. With the Acute Liver Failure Study Group Network, we are also investigating the potential for these biomarkers to serve as prognostic indicators of patient outcome.
Figure 1: Mechanisms of Acetaminophen Hepatotoxicity. Adapted from Jaeschke et al., Drug Metabolism Reviews 44: 88-106, 2012.
A renewed focus in the lab is liver injury caused by ischemia-reperfusion (I-R) during liver transplantation. Similar to our work on APAP hepatotoxicity, our goal is to better understand the mechanisms of injury using rodent models (including mitochondrial damage, oxidative stress, and kinase activation) and to translate these findings to humans.
In addition to studying hepatocytes during liver injury, we are interested in the roles played by the innate immune system in both the injury and subsequent regeneration. The innate immune response is critical in many liver disease processes. We have shown previously that polymorphonuclear leukocytes (neutrophils) aggravate liver injury during ischemia-reperfusion, endotoxemia and obstructive cholestasis in animal models. The mechanism of injury requires the upregulation of adhesion molecules on neutrophils, endothelial cells and hepatocytes, accumulation of neutrophils in sinusoids, extravasation and adhesion to target cells, which are subsequently killed by reactive oxygen species and proteases. The focus of our current investigations is to elucidate the inflammatory mediators involved in the extravasation process. In addition, we are evaluating intracellular signaling mechanisms of reactive oxygen-induced cell injury. The ultimate goal is to be able to selectively prevent neutrophil-induced liver injury in I-R and cholestasis without compromising the host-defense functions of the leukocytes. On the other hand, neutrophils appear to be important for liver regeneration and recovery after APAP overdose. Most of what we know about these processes has come from animal models. Now our lab is using this expertise and knowledge to advance our understanding of these mechanisms in human liver injury and disease. These translational studies evaluate the role of neutrophils during acute acetaminophen overdose and recovery, during obstructive cholestasis, and during liver transplantation and alcoholic hepatitis.
Figure 2: Acute necrotic cell death triggers an innate immune response, which can either aggravate the initial injury (A) or support recovery (B). Adapted from Jaeschke and Naisbitt, Immune mechanisms in drug-induced liver injury. In: Drug-Induced Liver Toxicity (Chen, M and Will, Y, eds.), in press, 2018.
Jaeschke, H., and Ramachandran, A.: Antioxidant defense mechanisms. In: McQueen, C. A., Comprehensive Toxicology, Third Edition. Vol. 2, pp. 277-295. Oxford: Elsevier Ltd, 2018.
Jaeschke, H., Bajt, M.L., and Ramachandran, A.: Mechanisms of acetaminophen hepatotoxicity: Cell death signaling mechanisms in hepatocytes. In: McQueen, C. A., Comprehensive Toxicology, Third Edition. Vol. 2, pp. 460-482. Oxford: Elsevier Ltd, 2018.
Ramachandran, A. and Jaeschke, H.: Oxidative stress and acute hepatic injury. Current Opinion in Toxicology 7: 17-21, 2018.
Li, J., Woolbright, B.L., Zhao, W., Wang Y., Matye, D., Hagenbuch, B., Jaeschke, H., Li, T.: Sortilin 1 loss-of-function protects against cholestatic liver injury by attenuating hepatic bile acid accumulation in bile duct ligated mice. Toxicological Sciences 161: 34-47, 2018. PMCID: PMC5837720
Woolbright, B.L., and Jaeschke, H.: Biomarkers of Mitochondrial Injury after Acetaminophen Overdose: Glutamate Dehydrogenase and Beyond. In: Mitochondrial Dysfunction and Environmental Toxicants, Volume 1. Will, Y., and Dykens, J.A., eds., John Wiley & Sons, Inc, pp. 373-382, 2018.
Willebrords, J., Maes, M., Veloso Alves Pereira, I., da Silva, T.C., Mollica Govoni, V., Veras Lopes, V., Crespo Yanguas, S., Shestopalov, V.I., Sayuri Nogueira, M., Alves de Castro, I., Farhood, A., Mannaerts, I., van Grunsven, L., Akakpo, J., Lebofsky, M., Jaeschke, H., Cogliati, B., Vinken, M.: Protective effect of genetic deletion of pannexin1 in experimental mouse models of acute and chronic liver disease. Biochimica et Biophysica Acta: Molecular Basis of Disease 1864: 819-830, 2018.
Jaeschke, H.: Mechanisms of sterile inflammation in acetaminophen hepatotoxicity. (Invited Editorial). Cellular & Molecular Immunology 15: 74-75, 2018.
Jaeschke, H.: Comments on caspase-mediated anti-apoptotic effect of Ginsenoside Rg5, a main rare ginsenoside, on acetaminophen-induced hepatotoxicity in mice (Commentary). Journal of Agricultural and Food Chemistry 66: 1732-1733, 2018.
Ramachandran, A. and Jaeschke, H.: Acetaminophen toxicity: Novel insights into mechanisms and future perspectives. Gene Expression: The Journal of Liver Research 18: 19-30, 2018.
Jaeschke, H., and Naisbitt, D.J.: Immune mechanisms in drug-induced liver injury. In: Drug-Induced Liver Toxicity, Chen, M. and Will, Y. (eds.), 1st edn. Humana Press, New York, pp. 511-531, 2018.
McGreal, S.R., Bhushan, B., Walesky, C., McGill, M.R., Lebofsky, M., Kandel, S.E., Winefield, R.D., Jaeschke, H., Zachara, N.E., Zhang, Z., Tan, E.P., Slawson, C., and Apte, U.: Modulation of O-GlcNAc levels in the liver impacts acetaminophen-induced liver injury by affecting protein adduct formation and glutathione synthesis. Toxicological Sciences 162: 599-610, 2018.
Woolbright, B.L. and Jaeschke, H.: Alcoholic hepatitis: Lost in translation. Journal of Clinical and Translational Hepatology 6: 89-96, 2018. PMCID: PMC5863004
Lutkewitte, A.J., Schweitzer, G.G., Kennon-McGill, S., Clemens, M.M., James, L.P., Jaeschke, H., Finck, B.N., and McGill, M.R.: Lipin deactivation after acetaminophen overdose causes phosphatidic acid accumulation in liver and plasma in mice and humans and enhances liver regeneration. Food and Chemical Toxicology 115: 273-283, 2018.
Jaeschke, H., and Ramachandran, A.: Reactive oxygen and lipid peroxidation in acetaminophen hepatotoxicity. Reactive Oxygen Species 5: 145-158, 2018.
Woolbright, B.L., and Jaeschke, H.: Is Keratin-18 only a marker of cell death in acute-on-chronic liver failure? (Invited Editorial). Journal of Laboratory and Precision Medicine 3: 26, 2018.
Borude, P., Bhushan, B., Gunewardena, S., Jaeschke, H., and Apte, U.: Pleiotropic role of p53 in injury and liver regeneration after acetaminophen hepatotoxicity. American Journal of Pathology 188: 1406-1418, 2018.
Jaeschke, H., Duan, L., Akakpo, J.Y., Farhood, A., and Ramachandran, A.: The role of apoptosis in acetaminophen-induced liver injury. Food and Chemical Toxicology 118: 709-718, 2018.
Chao, X., Wang, H., Jaeschke, H., and Ding, W.X.: Autophagy in acetaminophen-induced liver injury. Liver International 38: 1363-1374, 2018.
McGill, M.R. and Jaeschke, H.: Biomarkers of drug-induced liver injury: Progress and utility in research, medicine, and regulation. Expert Review of Molecular Diagnostics 18: 797-807, 2018.
Akakpo, J.Y., Ramachandran, A., Kandel, S.E., Ni, H.M., Kumer, S., Rumack, B.H., and Jaeschke, H.: 4-Methylpyrazole protects against acetaminophen hepatotoxicity in mice and in primary human hepatocytes. Human and Experimental Toxicology 37: 1310-1322, 2018. PMCID: PMC6482816
De Haan, L., van der Lely, S., Warps, A.L., Hofsink, P., Olthof, P.B., Lionarons, D.A., Mendes-Dias, L., Bruinsma, B.G., Uygun, K., Jaeschke, H., Farrell, G.C., Teoh, N., van Golen, R.F., Li, T., and Heger, M.: Post-hepatectomy liver regeneration in the context of bile acid homeostasis and the gut-liver signaling axis. Journal of Clinical and Translational Research 4: 1-46, 2018. PMCID: PMC6370335.
Ramachandran, A., Duan, L., Akakpo, J.Y., and Jaeschke, H.: Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future therapies (Invited Review). Journal of Clinical and Translational Research 4: 75-100, 2018. PMCID: PMC6261533.
Woolbright, B.L., and Jaeschke, H.: Mechanisms of inflammatory liver injury and drug-induced hepatotoxicity (Invited Review). Current Pharmacology Reports 4: 346-357, 2018. PMCID: PMC6294466
Duan, L., Ramachandran, A., Akakpo, J.Y., Weemhoff, J.L., Curry, S.C., and Jaeschke, H.: Role of exosomes in release of protein adducts after acetaminophen-induced liver injury in mice and humans. Toxicology Letters 301: 125-132, 2019. PMCID: PMC6338225
Roth, R.A., Jaeschke, H., and Luyendyk, J.P.: Toxic Responses of the Liver. (Invited Review). In: Casarett and Doull's Toxicology, 9th edition; (Klaassen, C.D., ed.), McGraw Hill Publishing, pp. 719-766, 2019.
Du, K., Ramachandran, A., Weemhoff, J.L., Woolbright, B.L., Jaeschke, A.H., Chao, X., Ding, W.X., and Jaeschke, H.: Mito-Tempo protects against acute liver injury but induces secondary apoptosis during the late phase of acetaminophen hepatotoxicity. Archives of Toxicology 93: 163-178, 2019. PMCID: PMC6344320.
Wang, H., Ni, H.M., Chao, X., Ma, X., Rodriguez, Y.A, Chavan, H., Wang, S., Krishnamurthy, P., Dobrowsky, R., Xu, D.X., Jaeschke, H. and Ding, W.X.: Double deletion of PINK1 and Parkin impairs hepatic mitophagy and exacerbates acetaminophen-induced liver injury in mice. Redox Biology 22: 101148, 2019. PMCID: PMC6395945.
Li, Y., Ni, H.M., Jaeschke, H., and Ding, W.X.: Chlorpromazine protects against acetaminophen-induced liver injury in mice by modulating autophagy, JNK and Nrf2 activation. Liver Research 3: 65-74, 2019.
Slowik, V.R., Borude, P., Woolbright, B.L., Jaeschke, H., Lee, W.M., and Apte, U.: Leukocyte Cell Derived Chemotaxin-2 (Lect2) as a predictor of survival in adult acute liver failure. Translational Gastroenterology and Hepatology 4: 17, 2019.
McGill, M.R., and Jaeschke, H.: Animal models for drug-induced liver disease (Invited Review). BBA-Molecular Basis of Disease 1865: 1031-1039, 2019.
Ramachandran, A., and Jaeschke, H.: Acetaminophen hepatotoxicity (Invited Review). Seminars in Liver Disease 39: 221-234, 2019.
Woolbright, B.L., and Jaeschke, H.: Measuring apoptosis and necrosis in cholestatic liver injury (Invited Review). In: Methods in Molecular Biology 1981: Experimental Cholestasis Research, M. Vinken (Ed.), Humana Press Inc., Totowa-USA, pp. 133-147, 2019.
Kennedy, R.C., Smith, A.K., Ropella, G.E.P., McGill, M.R., Jaeschke, H., and Hunt, C.A.: Propagation of pericentral necrosis during acetaminophen-induced liver injury: evidence for early inter-hepatocyte communication and information-exchange. Toxicological Sciences 169: 151-166, 2019.
Gijbels, E., Vilas-Boas, V., DeFerm, N., Devisscher, L., Jaeschke, H., Annaert, P. and Vinken, M.: Mechanisms and in vitro models of drug-induced cholestasis (Invited Review). Archives of Toxicology 93: 1169-1186, 2019.
Kennedy, J.L., Kurten, R.C., McCullough, S., Panettieri, R.A., Koziol-White, C.J., Jones, S.M., Roberts, D.W., Jaeschke, H., McGill, M.R., and James, L.P.: Acetaminophen is both bronchoprotective and bronchodilatory in human precision cut lung slice airways. Xenobiotica 49: 1106-1115, 2019.
Ni, H.M., Chao, X., Kasseff, J., Deng, F., Wang, S., Shi, Y.H., Li, T., Ding, W.X., and Jaeschke, H.: RIP3-MLKL-mediated necroptosis contributes to ischemia-reperfusion injury of steatotic livers. American Journal of Pathology 189: 1363-1374, 2019.
Akakpo, J.Y., Ramachandran, A., Duan, L., Schaich, M.A., Jaeschke, M.W., Freudenthal, B.D., Ding, W.X., Rumack, B.H., and Jaeschke, H.: Delayed treatment with 4-methylpyrazole protects against acetaminophen hepatotoxicity in mice by inhibition of c-jun N-terminal kinase. Toxicological Sciences 170: 57-68, 2019.
Ramachandran, A., and Jaeschke, H.: Acetaminophen hepatotoxicity - a mitochondrial perspective (Invited Review). Advances in Pharmacology 85: 195-219, 2019.
McGill, M.R., and Jaeschke, H.: Biomarkers of drug-induced liver injury (Invited Review). Advances in Pharmacology 85: 221-239, 2019.
Curry, S.C., Padilla-Jones, A., Ruha, A.M., O'Connor, A.D., Kang, A.M., Wilkins, D.G., Jaeschke, H., Wilhems, K., Gerkin, R.D., and The Acetaminophen Adduct Study Group. The relationship between circulating acetaminophen-protein adducts and alanine aminotransferase activity in patients with and without acetaminophen overdose and toxicity. Journal of Medical Toxicology 15: 143-155, 2019.
Ramachandran, A., and Jaeschke, H.: Hepatotoxins (Invited Review). In: Encyclopedia of Gastroenterology, 2nd edition, Ernst Kuipers, ed.; Elsevier, New York, in press, 2019.
Lemasters, J.J., and Jaeschke, H.: Oxidative stress and inflammation in the liver. In: The Liver. Biology and Pathobiology, 6th edition, I.M. Arias, H.J. Alter, J.L. Boyer, D.E. Cohen, N. Fausto, D.A. Shafritz, and A.W. Wolkoff (Eds.), Wiley-Blackwell, Chichester, West-Sussex, UK, in press, 2019.
Duan, L., Akakpo, J.Y., Ramachandran, A. and Jaeschke, H.: Environmental Liver Toxins (or Carcinogens). (Invited Review) In: Encyclopedia of Environmental Health, 2nd edition (J. Nriagu, ed.), in press, 2019.
Woolbright, B.L., and Jaeschke, H.: Inflammation and cell death in cholestatic liver injury: the evolving role of bile acids. Gene Expression, in press, 2019.
Jaeschke, H.: Emerging novel therapies for paracetamol (acetaminophen) hepatotoxicity (Invited Commentary). EBioMedicine, accepted.