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Hartmut Jaeschke, PhD

University Distinguished Professor & Chair
Ph.D., University of Tübingen, Germany, 1983


Research Focus

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.

Jaeschke Image 1Figure 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.

Jaeschke Image 2aJaeschke Image 2bFigure 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.

Selected ReferencesJaeschke Highly Cited Image

Ni, H.M., Bockus, A., Jaeschke, H., and Ding, W.X.: Activation of autophagy protects against acetaminophen hepatotoxicity in mice. Hepatology 55: 222-231, 2012.

Jaeschke, H., and Woolbright, B.L.: Current strategies to minimize hepatic ischemia-reperfusion injury by targeting reactive oxygen species. (Invited Review) Transplantation Reviews 26: 103-114, 2012.

McGill, M.R., Sharpe, M.R., Williams, C.D., Taha, M., Curry, S.C., and Jaeschke, H.: Mechanisms of acetaminophen hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. Journal of Clinical Investigation 122: 1574-1583, 2012.

Antoine, D.J., Jenkins, R.E., Dear, J.W., Williams, D.P., McGill, M.R., Sharpe, M.R., Craig, D.G., Simpson, K.J., Jaeschke, H., and Park, B.K.: Molecular forms of HMGB1 and Keratin-18 as mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity. Journal of Hepatology 56: 1070-1079, 2012.

McGill, M.R., Williams, C.D., Xie, Y., Ramachandran, A., and Jaeschke, H.: Acetaminophen-induced liver injury in rats and mice: Comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity. Toxicology and Applied Pharmacology 264: 387-394, 2012.

Ding, W.X., Guo, F., Ni, H.M., Bockus, A., Manley, S., Xie, T., Johnson, T., Stolz, D.B., Eskelinen E.-L., Jaeschke, H., and Yin, X.M.: Parkin and Mitofusins reciprocally regulate mitophagy and mitochondrial spheroid formation. Journal of Biological Chemistry 287: 42379-42388, 2012.

McGill, M.R., Lebofsky, M., Norris, H.R., Slawson, M.H., Bajt, M.L., Xie, Y., Williams, C.D., Wilkins, D.G., Rollins, D.E., and Jaeschke, H.: Plasma and liver acetaminophen-protein adducts and liver glutathione levels in mice after acetaminophen treatment: dose-response, mechanisms, and clinical implications. Toxicology and Applied Pharmacology 269: 240-249, 2013.

McGill, M.R., and Jaeschke, H.: Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis (Invited Review). Pharmaceutical Research 30: 2174-2187, 2013.

Ramachandran, A., McGill, M.R., Xie, Y., Ni, H.M., Ding, W.X., and Jaeschke, H.: The receptor interacting kinase protein 3 is a critical early mediator of acetaminophen-induced hepatocyte necrosis in mice. Hepatology 58: 2099-2108, 2013.

Woolbright, B.L., Antoine, D.J., Jenkins, R.E., Bajt, M.L., Park, B.K., and Jaeschke, H.: Plasma biomarkers of liver injury and inflammation demonstrate lack of apoptosis during obstructive cholestasis in mice. Toxicology and Applied Pharmacology 273: 524-531, 2013.

Yang, M., Ramachandran, A., Yan, H.M., Woolbright, B.L., Copple, B.L., Fickert, P., Trauner, M., and Jaeschke, H.: Osteopontin is an initial mediator of inflammation and liver injury during obstructive cholestasis after bile duct ligation in mice. Toxicology Letters 224: 186-195, 2014.

McGill, M.R., Li, F., Sharpe, M.R., Williams, C.D., Curry, S.C., Ma, X., and Jaeschke, H.: Acylcarnitines as biomarkers for mitochondrial dysfunction after acetaminophen overdose in mice and humans. Archives of Toxicology 88: 391-401, 2014.

Williams, C.D., Bajt, M.L., Sharpe, M.R., McGill, M.R., Farhood, A., and Jaeschke, H.: Neutrophil activation during acetaminophen hepatotoxicity and repair in mice and humans. Toxicology and Applied Pharmacology 275: 122-133, 2014.

McGill, M.R., Cao, M., Svetlov, A., Sharpe, M.R., Williams, C.D., Curry, S.C., Farhood, A., Jaeschke, H., and Svetlov, S.I.: Argininosuccinate synthetase is an early plasma biomarker of liver injury and active cell death during acetaminophen hepatotoxicity in mice and humans. Biomarkers 19: 222-230, 2014.

Ward, J., Kanchagar, C., Veksler-Lublinsky, I., Lee, R., McGill, M.R., Jaeschke, H., Curry, S.C., and Ambros, V.: Circulating microRNA profiles in human patients with acetaminophen hepatotoxicity and ischemic hepatitis. Proceedings of the National Academy of Sciences, USA 111: 12169-12174, 2014.

Ni, H.M., Woolbright, B.L., Williams, J., Copple, B.L., Cui, W., Luyendyk, J.P., Jaeschke, H., and Ding, W.X.: Nrf2 mediates the development of fibrosis and tumorigenesis in mice with a hepatocyte knock-out of autophagy. Journal of Hepatology 61: 617-625, 2014.

Xie, Y., McGill, M.R., Dorko, K., Kumer, S.C., Schmitt, T.M., Forster, J., and Jaeschke, H.: Mechanisms of acetaminophen-induced cell death in primary human hepatocytes. Toxicology and Applied Pharmacology 279: 266-274, 2014.

McGill, M.R., Staggs, V.S., Sharpe, M.R., Lee, W.M., Jaeschke, H., and Acute Liver Failure Study Group: Serum mitochondrial biomarkers and damage-associated molecular patterns are higher in acetaminophen overdose patients with poor outcome. Hepatology 60: 1336-1345, 2014.

Yang, M., Antoine, D.J., Weemhoff, J.L., Jenkins, R.E., Park, B.K., and Jaeschke, H.: Biomarkers distinguish apoptotic and necrotic cell death during hepatic ischemia-reperfusion injury in mice. Liver Transplantation 20: 1372-1382, 2014.

Woolbright, B.L., Dorko, K., Antoine, D.J., Clarke, J., Gholami, P., Li, F., Kumer, S.C., Schmitt, T.M., Forster, J., Fan, F., Jenkins, R.E., Park, B.K., Hagenbuch, B., Olyaee, M., and Jaeschke, H.: Bile acid-induced necrosis in primary human hepatocytes and in patients with obstructive cholestasis. Toxicology and Applied Pharmacology 283: 168-177, 2015.

Du, K., McGill, M.R., Bajt, M.L., Xie, Y., and Jaeschke, H.: Resveratrol prevents protein nitration and release of endonucleases from mitochondria during acetaminophen hepatotoxicity. Food and Chemical Toxicology 81: 62-70, 2015.

Xie, Y., Ramachandran, A., Breckenridge, D.G, Liles, J.T., Lebofsky, M., Farhood, A., and Jaeschke, H.: Inhibitor of apoptosis signal-regulating kinase 1 protects against acetaminophen hepatotoxicity in mice. Toxicology and Applied Pharmacology 286: 1-9, 2015.

Jaeschke, H.: Acetaminophen - dose-dependent drug hepatotoxicity and acute liver failure in patients (Invited Review). Digestive Diseases 33: 464-471, 2015.

Xie, Y., McGill, M.R., Cook, S.F., Sharpe, M.R., Winefield, R. D., Wilkins, D.G., Rollins, D.E., and Jaeschke, H.: Time course of acetaminophen-protein adducts and acetaminophen metabolites in circulation of overdose patients and in HepaRG cells. Xenobiotica 45: 921-929, 2015.

Du, K., Xie, Y., McGill, M.R. and Jaeschke, H.: Pathophysiological significance of c-jun N-terminal kinase in acetaminophen hepatotoxicity (Invited Review). Expert Opinion on Drug Metabolism and Toxicology 11: 1769-1779, 2015.

Xie, Y., McGill, M.R., Du, K., Dorko, K., Kumer, S.C., Schmitt, T.M., Ding, W.X., and Jaeschke, H.: Mitochondrial protein adducts formation and mitochondrial dysfunction contribute to N-acetyl-m-aminophenol (AMAP)-induced hepatotoxicity in primary human hepatocytes. Toxicology and Applied Pharmacology 289: 213-222, 2015.

McGill, M.R., Du, K., Weemhoff, J.L., and Jaeschke, H.: Critical review of resveratrol in xenobiotic-induced hepatotoxicity (Invited Review). Food and Chemical Toxicology 86: 309-318, 2015.

Maes, M., Vinken, M., and Jaeschke, H.: Experimental models of hepatotoxicity related to acute liver failure (Invited Review). Toxicology and Applied Pharmacology 290: 86-97, 2016.

Woolbright, B.L., McGill, M.R., Yan, H.M., and Jaeschke, H.: Bile acid-induced toxicity in HepaRG cells recapitulates the response in primary human hepatocytes. Basic & Clinical Pharmacology and Toxicology 118: 160-167, 2016.

Hu, J.T., Ramshesh, V.K., McGill, M.R., Jaeschke, H., and Lemasters, J.J.: Low dose acetaminophen induces reversible mitochondrial dysfunction associated with transient c-jun N-terminal kinase activation in mouse liver. Toxicological Sciences 150: 204-215, 2016.

Hu, J.T., Kholmukhamedov, A., Lindsey, C., Beeson, C., Jaeschke, H., and Lemasters J.J.: Translocation of iron from lysosomes to mitochondria during acetaminophen-induced hepatocellular injury: Protection by starch-desferal and minocycline. Free Radical Biology and Medicine 97: 418-426, 2016.

Ni, H.M., McGill, M.R., Chao, X.J., Du, K., Williams, J.A., Xie, Y., Dorko, K., Jaeschke, H., and Ding, W.X.: Removal of acetaminophen-protein adducts by autophagy protects against acetaminophen-induced liver injury in mice. Journal of Hepatology 65: 354-362, 2016. 

Ni, H.M., McGill, M.R., Chao, X.J., Woolbright, B.L., Jaeschke, H., and Ding, W.X.: Caspase inhibition prevents TNF-α-induced apoptosis and promotes necrotic cell death in mouse hepatocytes in vivo and in vitro. American Journal of Pathology 186: 2623-2636, 2016.

Du, K., Ramachandran, A., and Jaeschke, H.: Oxidative stress during acetaminophen hepatotoxicity: Sources, pathophysiological role and therapeutic potential (Review). Redox Biology 10: 148-156, 2016. 

Duan, L., Davis, J.S., Woolbright, B.L., Du, K., Cahkraborty, M., Weemhoff, J.L., Jaeschke, H., and Bourdi, M.: Differential susceptibility to acetaminophen-induced liver injury in sub-strains of C57BL/6 mice: 6N versus 6J. Food and Chemical Toxicology 98: 107-118, 2016. 

Du, K., Ramachandran, A., Weemhoff, J.L., Chavan, H., Xie, Y., Krishnamurthy, P., and Jaeschke, H.:  Metformin protects against acetaminophen hepatotoxicity by attenuation of mitochondrial oxidant stress and dysfunction. Toxicological Sciences 154: 214-226, 2016. 

Woolbright, B.L., Williams, C.D., Ni, H.M., Kumer, S., Schmitt, T., Kane, B., and Jaeschke, H.:  Oncotic necrosis predominates microcystin-LR induced liver injury in primary human hepatocytes. Toxicon 125: 99-109, 2017.

Du, K., Farhood, A., and Jaeschke H.: Mitochondria-targeted antioxidant Mito-Tempo protects against acetaminophen hepatotoxicity. Archives of Toxicology 91: 761-773, 2017. 

Bhushan, B., Chavan, H., Borude, P., Xie, Y., Du, K., McGill, M.R., Lebofsky, M., Jaeschke, H., Kasturi, P., and Apte, U.: Dual role of epidermal growth factor receptor in liver injury and regeneration after acetaminophen overdose in mice. Toxicological Sciences 155: 363-378, 2017.

Weemhoff, J.L., Woolbright, B.L., Jenkins, R.E., McGill, M.R., Sharpe, M.R., Olson, J.C., Antoine, D.J., Curry, S.C., and Jaeschke, H.: Plasma biomarkers to study mechanisms of liver injury in patients with hypoxic hepatitis. Liver International 37: 377-384, 2017. 

Woolbright, B.L., and Jaeschke, H.: Role of the inflammasome in acetaminophen-induced liver injury and acute liver failure (Invited Review). Journal of Hepatology 66: 836-848, 2017. 

Woolbright, B.L., and Jaeschke, H.: Mechanisms of acetaminophen-induced liver injury. In: Cellular Injury in Liver Diseases, Ding, WX, Yin, XM (eds.), Springer Int. Publ., pp. 55-76, 2017.

Ramachandran, A., and Jaeschke, H.: Acetaminophen. In: Liver Pathophysiology: Therapies and Antioxidants, Muriel, P. (ed.), Elsevier, pp. 101-112, 2017.

Ramachandran, A., and Jaeschke, H.: Intracellular signaling mechanisms of acetaminophen-induced cell death and their translation to the human pathophysiology (Invited Review). Journal of Clinical and Translational Research 3(S1): 157-169, 2017. 

Woolbright, B.L., and Jaeschke, H.: The impact of sterile inflammation in acute liver injury (Invited Review). Journal of Clinical and Translational Research 3(S1): 170-188, 2017. 

Maes, M., McGill, M.R., da Silva, T.C., Abels, C., Lebofsky, M., Weemhoff, J.L.,  Tiburcio, T., Veloso Alves Pereira, I., Willebrords, J., Crespo Yanguas, S., Farhood, A., Beschin, A., Van Ginderachter, J.A., Penuela, S., Jaeschke, H., Cogliati, B., and Vinken, M. Inhibition of pannexin1 channels alleviates acetaminophen-induced hepatotoxicity. Archives of Toxicology 91: 2245-2261, 2017. 

Maes, M., Crespo Yanguas, Willebrods, J., Weemhoff, J.L., da Silva, T.C., Decrock, E., Lebofsky, M., Veloso Alves Pereira, I., Leybaert L., Farhood, A., Jaeschke, H., Cogliati, B., and Vinken, M.: Connexin hemichannel blocking reduces drug-induced liver injury in mice. Toxicology Letters 278: 30-37, 2017. 

Du, K., Ramachandran, A., McGill, M.R., Mansouri, A., Asselah, T., Farhood, A., Woolbright, B.L., Ding, W.X., and Jaeschke, H.: Induction of mitochondrial biogenesis protects against acetaminophen hepatotoxicity. Food and Chemical Toxicology 108: 339-350, 2017.

Woolbright, B.L., Bridges, B.W., Dunn, W., Olson, J., Weinman, S.A., and Jaeschke, H.: Cell death and prognosis of mortality in alcoholic hepatitis patients using plasma keratin-18. Gene Expression: The Journal of Basic Liver Research 17: 301-312, 2017.

Ramachandran, A. and Jaeschke, H.: Oxidative Stress and Acute Hepatic Injury. Current Opinion in Toxicology 7: 17-21, 2018.

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.

Jaeschke, H.: Mechanisms of sterile inflammation in acetaminophen hepatotoxicity. (Invited Editorial). Cellular & Molecular Immunology, in press.

Roth, R.A., Jaeschke, H., and Luyendyk, J.P.: Toxic Responses of the Liver. In: Casarett and Doull's Toxicology, 9th edition; (Klaassen, C.D., ed.), McGraw Hill Publishing, in press, 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.), in press, 2018.

Ramachandran, A. and Jaeschke, H.: Acetaminophen toxicity: Novel insights into mechanisms and future perspectives (Invited Review). Gene Expression: The Journal of Basic Liver Research, in press, 2018.

Woolbright, B.L. and Jaeschke, H.: Alcoholic Hepatitis: Lost in translation (Invited Review). Journal of Clinical and Translational Hepatology, in press, 2018. 

Last modified: Jun 28, 2019

hjaeschke

Contact

Hartmut Jaeschke, PhD
University Distinguished Professor & Chair

4098 HLSIC; MS-1018
3901 Rainbow Blvd.
Kansas City, Kansas 66160

P: (913) 588-7500
hjaeschke@kumc.edu

Curriculum Vitae

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