Hartmut Jaeschke, PhD

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. For example, we have recently shown that the kinase RIP3 is critically involved in APAP toxicity at early time points after APAP intoxication in mice. Not content to stop at rodents, 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 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.

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 ischemic injury.


Selected Publication

Jaeschke, H., Williams, C.D., Ramachandran, A., and Bajt, M.L.: Acetaminophen hepatotoxicity and repair: role of sterile inflammation and innate immunity (Invited Review). Liver International 32: 8-20, 2012.

Zhang Y., Hong, J.Y., Rockwell, C.E., Copple, B.L., Jaeschke, H., and Klaassen, C.D. Effect of bile duct ligation on bile acid composition in mouse serum and liver. Liver International 32: 58-69, 2012.

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., McGill, M.R., and Ramachandran, A.: Oxidant stress, mitochondria and intracellular cell death mechanisms in drug-induced liver injury: Lessons learned from acetaminophen hepatotoxicity (Invited Review). Drug Metabolism Reviews 44: 88-106, 2012.

Ni, H.M., Jaeschke, H., and Ding, W.X.: Targeting autophagy for drug-induced hepatotoxicity (Invited Commentary). Autophagy 8: 709-710, 2012.

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

Jaeschke, H.: Therapeutic strategies against ischemia-reperfusion injury: Stem cell therapy and beyond (Invited Commentary). Critical Care Medicine 40: 1381-1382, 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.

Kong, B., Csanaky, I.L., Aleksunes, L.M., Patni, M., Chen, Q., Ma, X. Jaeschke, H., Weir, S., Broward, M., Klaassen, C.D., Guo, G.L.: Gender-specific reduction of hepatic Mrp2 expression by high-fat diet protects female mice from ANIT toxicity. Toxicology and Applied Pharmacology 261: 189-195, 2012.

Ni, H.M., Boggess, N., McGill, M.R., Lebofsky, M., Borude, P., Apte, U., Jaeschke, H., and Ding, W.X.: Liver specific loss of Atg5 causes persistent activation of Nrf2 and protects against acetaminophen-induced liver injury. Toxicological Sciences 127: 438-450, 2012.

Jaeschke, H., and Ding, W.X.: Autophagy and acetaminophen hepatotoxicity: How useful are Atg7-deficient mice? (Letter). Journal of Gastroenterology 47: 845-846, 2012.

Aubert, J., Begriche, K., Delannoy, D., Morel, I., Pajaud, J., Ribault, C., Lepage, S., McGill, M.R., Lucas-Clerc, C., Turlin, B., Robin, M.A., Jaeschke, H., and Fromenty, B.: Early acetaminophen hepatotoxicity in obese and diabetic mice is not related to the degree of fatty liver. Journal of Pharmacology and Experimental Therapeutics 342: 676-687, 2012.

Woolbright, B.L., and Jaeschke, H.: Novel insight into the mechanisms of cholestatic liver injury (Invited Review). World Journal of Gastroenterology 18: 4985-4993, 2012.

Williams, C.D., and Jaeschke, H.: Role of the innate and adaptive immunity during drug-induced liver injury (Invited Review). Toxicology Research 1: 161-170, 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.

Jaeschke, H., Williams, C.D., and McGill, M.R.: Caveats of using acetaminophen hepatotoxicity models for natural product testing (Letter). Toxicology Letters 215: 40-41, 2012.

Woolbright, B.L., Ramachandran, A., McGill, M.R., Yan, H.M., Bajt, M.L., Sharpe, M.R., Lemasters, J.J., and Jaeschke, H.: Lysosomal instability and cathepsin B release during acetaminophen hepatotoxicity. Basic & Clinical Pharmacology and Toxicology 111: 417-425, 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.

Xie, Y., Williams, C.D., McGill, M.R., Lebofsky, M., Ramachandran, A., and Jaeschke, H.: Purinergic receptor antagonist A438079 protects against acetaminophen-induced liver injury by inhibiting P450 isoenzymes but not inflammasome activation. Toxicological Sciences 131: 325-335, 2013.

Jaeschke, H., McGill, M.R. and Williams, C.D.: The pathophysiological relevance of neutrophils in acetaminophen hepatotoxicity (Letter). Hepatology 57: 419, 2013.

Jaeschke, H., Williams, C.D., McGill, M.R., Xie, Y., and Ramachandran, A.: Models of drug-induced liver injury for evaluation of phytotherapeutics and other natural products (Review).  Food and Chemical Toxicology, in press, 2013.

Last modified: Aug 19, 2013

hjaeschke

Contact

Hartmut Jaeschke, PhD
Professor & Chair

4085 HLSIC; MS-1018
3901 Rainbow Blvd.
Kansas City, Kansas 66160

P: (913) 588-7969
F: (913) 588-7501
hjaeschke@kumc.edu

Curriculum Vitae

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