Research Interests
To investigate the molecular mechanisms of apoptotic and oncotic cell injury in vivo and in primary cultured hepatocytes

• Neutrophil-induced liver injury: the role of reactive oxygen species, adhesion molecules, cytokines and chemokines
• Drug-induced hepatotoxicity: the role of reactive oxygen and peroxynitrite in modulating intracellular signaling pathways and regeneration
• Susceptibility of diet-induced steatotic (fatty) livers to cell injury

We have shown previously in several liver disease processes, including ischemia-reperfusion injury, endotoxin shock and obstructive cholestasis, that neutrophils aggravate the existing liver injury. 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 a target cell, which is subsequently killed by reactive oxygen species. The focus of 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 injury, oxidant stress and peroxynitrite formation 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 strategies of intervention, which prevent liver failure and improve survival.

Non-alcoholic 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 are at risk to progress to steatohepatitis and later to cirrhosis. The focus of our investigation is to assess how diet-induced steatosis affects the susceptibility of liver cells to secondary insults and how it impairs regeneration.

Selected Publications

Dorman R, Gujral JS, Bajt ML, Farhood A, Jaeschke H. Generation and functional significance of CXC chemokine formation for neutrophil-induced liver injury during endotoxemia. American Journal of Physiology Gastrointest Liver Physiol 288: G880-G886, 2005.

Cover C, Fickert P, Knight TR, Fuchsbichler A, Farhood A, Trauner M, Jaeschke, H. Pathophysiological role of poly(ADP-ribose) polymerase (PARP) activation during acetaminophen-induced liver cell necrosis in mice. Toxicological Sciences 84: 201-208, 2005.

Hasegawa T, Malle E, Farhood A, 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 TR, Bajt ML, Lemasters JJ, Pessayre D, 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, Bajt ML. Intracellular signaling mechanisms of acetaminophen-induced liver cell death. (Invited Review) Toxicological Sciences 89: 31-41, 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, in press, 2006.

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