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
Hasegawa, T., Malle, E., Farhood, A., and Jaeschke, H.: Generation of hypochlorite-modified proteins by neutrophils during ischemia-reperfusion injury in rat liver: attenuation by ischemic preconditioning. American Journal of Physiology Gastrointest Liver Physiol 289: 760-767, 2005.
Jaeschke, H.: Role of inflammation in the mechanism of acetaminophen-induced hepatotoxicity (Invited Review). Expert Opinions on Drug Metabolism and Toxicology, 1: 389-397, 2005.
Cover, C., Mansouri, A., Knight, T.R., Bajt, M.L., Lemasters, J.J., Pessayre, D., and Jaeschke, H.: Peroxynitrite-induced mitochondrial and endonuclease-mediated nuclear DNA damage in acetaminophen hepatotoxicity. Journal of Pharmacology and Experimental Therapeutics 315: 879-887, 2005.
Jaeschke, H., and Bajt, M.L.: Intracellular signaling mechanisms of acetaminophen-induced liver cell death. (Invited Review) Toxicological Sciences 89: 31-41, 2006.
Jaeschke, H., Cover, C., and Bajt, M.L.: Role of caspases in acetaminophen-induced liver injury. Life Sciences 78: 1670-1676, 2006.
Fickert, P., Fuchsbichler, A., Marschall, H.U., Wagner, M., Zollner, G., Krause, R., Zatloukal, K., Jaeschke, H., Denk, H., and Trauner, M.: Lithocholic acid feeding induces segmental bile duct obstruction and destructive cholangitis in mice. American Journal of Pathology 168: 410-422, 2006.
Fickert, P., Wagner, M., Marschall, H.U., Fuchsbichler, A., Zollner, G., Tsybrovskyy O., Zatloukal, K., Liu, J., Waalkes, M.P., Cover, C., Denk, D., Hofmann, A.F., Jaeschke, H., and Trauner, M. 24-norUrsodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 130: 465-481, 2006.
Jaeschke, H.: Mechanisms of neutrophil-mediated liver cell injury during ischemia-reperfusion and other acute inflammatory conditions. (Invited Review). American Journal of Physiology Gastrointestinal and Liver Physiology 290: G1083-G1088,2006.
Jaeschke, H.: Mechanisms of liver cell destruction (Invited Review). In Zakim and Boyer’s Hepatology, 5th edition. (Boyer, T.D., Wright, T.L., Manns, M., eds); Saunders, Elsevier, 2006; pp. 37-51.
Ito, Y., Abril, E.R., Bethea, N.W., McCuskey, M.K., Cover, C., Jaeschke, H., and McCuskey, R.S.: Mechanisms and pathophysiological implications of sinusoidal endothelial cell gap formation following treatment with galactosamine/endotoxin in mice. American Journal of Physiology Gastrointestinal and Liver Physiology 291: G211-G218, 2006.
Cover, C., Liu, J., Farhood, A., Malle, E., Waalkes, M.P., Bajt, M.L., and Jaeschke, H.: Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity. Toxicology and Applied Pharmacology, in press, 2006; Jun 15; [Epub ahead of print].
Bajt, M.L., Cover, C., Lemasters, J.J., and Jaeschke, H.: Nuclear translocation of endonuclease G and apoptosis-inducing factor during acetaminophen-induced liver injury. Toxicological Sciences, in press, 2006; Aug 8; [Epub ahead of print].
Contact Information
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 9/6/06
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The University of Kansas Medical Center