Pharmacology, Toxicology and Therapeutics : Faculty & Graduate Students : Hartmut Jaeschke
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
Jaeschke, H.: Troglitazone hepatotoxicity: Are we getting closer to understanding the pathophysiology of idiosyncratic liver injury? (Invited Editorial Comment) Toxicological Sciences 97: 1-3, 2007.
Jaeschke, H.: Kupffer Cells. In “Textbook of Hepatology: From Basic Science to Clinical Practice, 3rd edition”. (Rodes, J., Benhamou, J.P., Blei, A.T., Reichen, J., Rizzetto, M., eds.) Blackwell Publishing, pp.36-42, 2007.
Jaeschke, H., and Liu, J.: Neutrophil depletion protects against murine acetaminophen hepatotoxicity: Another perspective. (Letter). Hepatology 45: 1588-1589, 2007.
Hasegawa, T., Ito, Y., Wijeweera, J., Liu, J., Malle, E., Farhood, A., McCuskey, R.S., and Jaeschke, H.: Reduced inflammatory response and increased microcirculatory disturbances during hepatic ischemia-reperfusion injury in steatotic livers of ob/ob mice. American Journal of Physiology Gastrointestinal and Liver Physiology 292: G1385-G1395, 2007.
Fickert, P., Stöger, U., Fuchsbichler, A., Moustafa, T., Marschall, H.-U., Weiglein A.H., Tsybrovskyy, O., Jaeschke, H., Zatloukal K., Denk, H., and Trauner, M.: A new xenobiotic-induced mouse model of sclerosing cholangitis and biliary fibrosis. American Journal of Pathology 171: 525-536, 2007.
Ramaiah, S.K., and Jaeschke, H.: Hepatic neutrophil infiltration in the pathogenesis of alcohol-induced liver injury (Invited Review). Toxicology Mechanisms and Methods 17: 431-440, 2007.
Wagner, M., Zollner, G., Fickert, P., Gumhold, J., Silbert, D., Fuchsbichler, A., Gujral, J.S., Zatloukal, K., Denk, H., Jaeschke, H., and Trauner, M.: Hepatobiliary transporter expression in ICAM-/- and lpr mice after common bile duct ligation is independent of the degree of inflammation and oxidative stress. Drug Metabolism & Disposition 35: 1694-1699, 2007.
Ramaiah, S.K., and Jaeschke, H.: Role of neutrophils in the pathogenesis of acute inflammatory liver injury (Invited Review). Toxicologic Pathology 35: 757-766, 2007.
Jaeschke, H.: Toxic Responses of the Liver. In: Casarett and Doull's Toxicology, 7th edition; (Klaassen, C.D., ed.) McGraw Hill Publ., pp. 557-582, 2007.
Jaeschke, H.: Antioxidant Defense in Liver Injury: Oxidative Stress, Antioxidant Defense and Liver Injury. In: Drug-induced Liver Disease, 2nd edition; (Kaplowitz, N., and DeLeve, L.D., eds.), Marcel Dekker, Inc., New York, pp. 33-48, 2007.
Bajt, M.L., Farhood, A., Lemasters, J.J., and Jaeschke, H.: Mitochondrial Bax translocation accelerates DNA fragmentation and cell necrosis in a murine model of acetaminophen hepatotoxicity. Journal of Pharmacology & Experimental Therapeutics 324: 8-14, 2008.
Andringa, K.K., Bajt, M.L., Jaeschke, H., and Bailey, S.M.: Mitochondrial protein thiol modifications in acetaminophen hepatotoxicity: effect on HMG-CoA synthase. Toxicology Letters 177: 188-197, 2008.
Jaeschke, H. and Hong, J.Y.: Apoptosis and oncotic necrosis: profibrotic signalling mechanisms of cell death. In: Liver Cirrhosis: From Pathophysiology to Disease Management (Falk Symposium 162); (Bosch, J., Burroughs, A.K., Lammert, F., Lebrec, D., Sauerbruch, T., eds.), Springer Verlag, Berlin, pp. 3-10, 2008.
Bajt, M.L., Yan, H.-M., Farhood, A., and Jaeschke, H.: Plasminogen activator inhibitor-1 limits liver injury and facilitates regeneration after acetaminophen overdose. Toxicological Sciences 104: 419-427, 2008.
Jaeschke, H.: Innate immunity and acetaminophen-induced liver injury: why so many controversies? (Invited Editorial Comment). Hepatology 48: 699-701, 2008.
Uchiyama, A., Kim, J.S., Kon, K., Jaeschke, H., Ikejima, K., Watanabe, S., and Lemasters, J.J.: Translocation of iron from lysosomes into mitochondria is a key event during oxidative stress-induced hepatocellular injury. Hepatology 48: 1644-1654, 2008.
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.
Jaeschke, H. and Bajt, M.L.: Mechanisms of acetaminophen hepatotoxicity. In: Comprehensive Toxicology (McQueen, C.A., ed.), Volume X: Hepatic Toxicology (Roth, R.A., Ganey, P., eds), Elsevier, Oxford, in press, 2009.
Jaeschke, H.: Cellular antioxidant defense mechanisms. In: Comprehensive Toxicology (C.A. McQueen, ed.), Volume IX: Hepatic Toxicology (Roth, R.A., Ganey, P., eds), Elsevier, Oxford, in press, 2009.
Lemasters, J.J., Uchijama, 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, J.L. Boyer, F.V. Chisari, N. Fausto, D. Schachter, and D.A. Shafritz (Eds.), Lippincott, Williams &Wilkins, Philadelphia, in press, 2009.
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, 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, in press, 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, in press, 2009.
Hartmut Jaeschke, PhD
Professor
Department of Pharmacology, Toxicology & Therapeutics
The University of Kansas Medical Center
MS 1018, 3901 Rainbow Blvd.
Kansas City, KS 66160
Phone: (913) 588-7969
Fax: (913) 588-7501
Email: hjaeschke@kumc.edu
Updated 8/14/09
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The University of Kansas Medical Center