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.

The innate immune response plays a critical role in many liver disease processes. We have shown previously that polymorphonuclear leukocytes (neutrophils) aggravate liver injury during ischemia-reperfusion, endotoxemia and obstructive cholestasis. 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 without compromising the host-defense functions of the leukocytes.

A second focus of the laboratory is to understand mechanisms of acetaminophen-induced liver cell injury and regeneration in experimental animals and humans. Acetaminophen overdose is the most frequent cause of drug-induced liver failure in the US and the UK. We are evaluating the role of mitochondrial dysfunction, oxidant stress and peroxynitrite formation, MAP and RIP kinase activation, mitochondrial and nuclear DNA fragmentation in the mechanisms cell injury in mouse hepatocytes and in humans. Development of novel biomarker of tissue injury and their application to predicting development of liver failure is being pursued. In addition, the role of autophagy, especially mitophagy, as adaptive defense against APAP-induced cell death is being investigated in collaboration with Dr. Ding. Furthermore, we are investigating signaling mechanisms of regeneration and the role of inflammation in promoting tissue repair. The goal is to develop novel therapeutic strategies, which prevent drug-induced liver failure and improve survival.

Nonalcoholic fatty liver disease (NAFLD) is a condition affecting 14 - 21% of adults in Europe, Japan and the US. Although the early stage of NAFLD, i.e. steatosis, is considered benign by itself, patients exposed to secondary insults are at risk to progress to steatohepatitis and later to cirrhosis. The focus of our current investigation is to assess the molecular mechanisms for the increased susceptibility of steatotic livers to secondary insults such as ischemia-reperfusion and how steatosis impairs regeneration.

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.