Hartmut Jaeschke, Ph.D.

 

Ph.D., University of Tübingen, Germany, 1983

Curriculum Vitae

Research Interests

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. 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, mitochondrial and nuclear DNA fragmentation in cell injury. In addition, we are investigating signaling mechanisms of regeneration and assessing how acetaminophen toxicity affects cell cycle regulation. 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 Publications

Hong, J.Y., Lebofsky, M., Farhood, A., and Jaeschke, H.: Oxidant stress-induced liver injury in vivo: role of apoptosis, oncotic necrosis and JNK activation. American Journal of Physiology Gastrointestinal and Liver Physiology 296: G572-G581, 2009.

Smedsrod, B., LeCouteur, D., Ikejima, K., Jaeschke, H., Kawada, N., Naito, M., Knolle, P., Nagy, L., Senoo, H., Vidal-Vanaclocha, V., Yamaguchi, N.: Hepatic sinusoidal cells in health and disease: Updatefrom the 14th International Symposium. Liver International 29: 490-501, 2009.

Jaeschke, H.: Reactive oxygen species, hypohalites, and reactive nitrogen species in liver pathophysiology. In: Endogenous Toxins: Diet, Genetics, Disease and Treatment (O’Brien, P.J., Bruce, W.R., eds.) Wiley-VCH Verlag, pp. 249-266, 2009.

Nalapardeddy, P., Schüngel, S., Hong, J.Y., Manns, M.P., Jaeschke, H., and Vogel, A.: The BH3-only protein Bid does not mediate death-receptor-induced liver injury in obstructive cholestasis. American Journal of Pathology 175: 1077-1085, 2009.

Schüngel, S., Buitrago-Molina, L.E., Devi, P., Lebofsky, M., Manns, M.P., Jaeschke, H., Gross, A., and Vogel, A.: The strength of the Fas ligand signal determines whether hepatocytes act as type I or type II cells in murine livers. Hepatology 50: 1558-1566, 2009.

Fickert, P., Fuchsbichler, A., Moustafa, T., Wagner, M., Zollner G., Halilbasic, E.,  Stöger, U., Arrese, M., Pizarro, M., Solís, N., Carrasco, G., Caligiuri, A., Sombetzki, M., Reisinger, E., Tsybrovskyy, O., Zatloukal, K., Denk, H., Jaeschke, H., Pinzani, M., and Trauner, M.: Farnesoid X receptor critically determines the fibrotic response in mice but is expressed to a low extent in human hepatic stellate cells and periductal myofibroblasts. American Journal of Pathology 175: 2392-2405, 2009.

Lemasters, J.J., Uchiyama, A., Kim, J.S., Kon, K., and Jaeschke, H.: Role of intracellular iron movement and oxidant stress in hepatocellular injury. In: The Liver. Biology and Pathobiology, 5th 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, pp. 511-520, 2009.

Saito, C., Yan, H.M., Artigues, A., Vittal, M.T., Farhood, A., and Jaeschke, H.: Mechanism of protection by metallothionein against acetaminophen hepatotoxicity. Toxicology and Applied Pharmacology 242: 182-190, 2010.

Saito, C., Zwingmann, C., Jaeschke, H.: Novel mechanisms of protection against acetaminophen hepatotoxicity in mice by glutathione and N-acetylcysteine. Hepatology 51: 246-254, 2010.

Jaeschke, H.: DAMPen danger signals: Novel therapeutic strategies against post-ischemic inflammation (Invited Editorial). Critical Care Medicine 38: 998-999, 2010.

Copple, B.L., Jaeschke, H., and Klaassen, C.D.: Oxidative stress and the pathogenesis of cholestasis (Invited Review). Seminars in Liver Disease 30: 195-204, 2010.

Jaeschke, H., Williams, C.D., McGill, M.R., and Farhood, A.:  Herbal extracts as hepatoprotectants against acetaminophen hepatotoxicity. World Journal of Gastroenterology 16(19): 2448-2450, 2010.

Fickert, P., Thueringer, A., Moustafa, T., Silbert, D., Gumhold, J., Tsybrovskyy, O., Lebofsky, M., Jaeschke, H., Denk, H., and Trauner, M.: Role of osteopontin and tumor necrosis factor alpha receptor-1 in xenobiotic-induced cholangitis and biliary fibrosis in mice. Laboratory Investigation 90: 844-852, 2010.

Adams, D.H., Ju, C., Ramaiah, S., Uetrecht, J.P. and Jaeschke, H.: Mechanisms of immune-mediated liver injury (Review). Toxicological Sciences 115: 307-321, 2010.

Saito, C., Lemasters, J.J., and Jaeschke, H.: c-Jun-N-terminal kinase modulates oxidant stress and peroxynitrite formation independent of inducible nitric oxide synthase in acetaminophen hepatotoxicity. Toxicology and Applied Pharmacology 246: 8-17, 2010.

Jaeschke, H. and Bajt, M.L.: Mechanisms of Acetaminophen Hepatotoxicity. In: C.A. McQueen, ed.; Comprehensive Toxicology, volume 9, pp. 457–473; Oxford: Academic Press, 2010.

Jaeschke, H.: Antioxidant Defense Mechanisms. In: C.A. McQueen, ed.; Comprehensive Toxicology, volume 9, pp. 319–337. Oxford: Academic Press, 2010.

Kon, K., Kim, J.S., Uchiyama, A., Jaeschke, H., and Lemasters, J.J.: Lysosomal iron mobilization and induction of the mitochondrial permeability transition in acetaminophen-induced toxicity to mouse hepatocytes. Toxicological Sciences 117: 101-108, 2010.

Williams, C.D., Farhood, A., and Jaeschke, H.: Role of caspase-1 and interleukin-1β in acetaminophen-induced hepatic inflammation and liver injury. Toxicology and Applied Pharmacology 247: 169-178, 2010.

Williams, C.D., Bajt, M.L., Farhood, A., and Jaeschke, H.: Acetaminophen-induced hepatic neutrophil recruitment and liver injury in CD18-deficient mice. Liver International 30: 1280-1292, 2010.

Yan, H.M., Ramachandran, A., Bajt, M.L., Lemasters, J.J., and Jaeschke, H.: The oxygen tension modulates acetaminophen-induced mitochondrial oxidant stress and cell injury in primary cultured hepatocytes. Toxicological Sciences 117: 515-523, 2010.

Williams, C.D. and Jaeschke, H.: Liver toxicology. In: Encyclopedia of Environmental Health (J. Nriagu, ed), Section: Toxicology (S. Ansari, ed), Elsevier, Oxford, in press, 2011.

Jaeschke, H.: Toxicant-induced liver injury. In: Molecular Pathology of Liver Diseases (S.P. Monga, ed), Springer Verlag, Berlin, in press, 2010.

Jaeschke, H., Williams, C.D., and Farhood, A.: No evidence for caspase-dependent apoptosis in acetaminophen hepatotoxicity (Letter). Hepatology, in press, 2010.

Ramachandran, A., Lebofsky, M., Baines, C., Lemasters, J.J., and Jaeschke, H.: Cyclophilin D deficiency protects against acetaminophen-induced oxidant stress and liver injury. Free Radical Research, in press, 2010.

Allen, K., Jaeschke, H., and Copple, B.L.: Bile acids induce inflammatory genes in hepatocytes: a novel mechanism of inflammation during obstructive cholestasis. American Journal of Pathology, in press, 2010.

Jaeschke, H., Yan, H.M., and Ramachandran, A.: Reactive nitrogen species in acetaminophen-induced mitochondrial damage and toxicity in mouse hepatocytes – a cautionary note on the impact of cell culture conditions. (Letter). Chemical Research in Toxicology, in press, 2010.  

 

Contact Information

Hartmut Jaeschke, Ph.D.
Professor & Chair
Department of Pharmacology, Toxicology & Therapeutics
The University of Kansas Medical Center
4085 HLSIC; MS 1018
3901 Rainbow Boulevard
Kansas City, KS 66160
Phone: (913) 588-7969
Fax: (913) 588-7501
Email: hjaeschke@kumc.edu

Updated 1/11/12