Ischemia-reperfusion (IRP) injury is an important clinical problem, which determines morbidity and mortality after liver transplantation, liver surgery and hemorrhagic or septic shock. IRP injury is an even bigger issue in steatotic livers. A self-perpetuating inflammatory response is a key component of the overall tissue injury during reperfusion. Resident macrophages (Kupffer cells) and recruited neutrophils are the main cell types directly responsible for parenchymal cell damage. Reactive oxygen species (ROS) generated by these inflammatory cells diffuse into hepatocytes and trigger an intracellular oxidant stress, which ultimately causes necrotic cell death. Sulfhydryl groups can provide the necessary electrons to reductively inactivate these ROS. Therefore, we hypothesize that strengthening the endogenous antioxidant capacity in target cells may be most effective in preventing cell injury by Kupffer cells and neutrophils and thereby attenuating the inflammatory response without compromising vital host-defense functions of these cells. Metallothioneins (MTs) are sulfhydryl-rich polypeptides, which contain 18-23 cysteine residues per molecule. MT-1 and MT-2 are highly inducible genes and have been shown to be effective scavengers of ROS in vitro. However, virtually nothing is known about the induction of MTs during hepatic IRP or ischemic preconditioning in both lean and steatotic livers. Therefore, the overall aims of this proposal are to provide a comprehensive analysis of the postischemic gene expression of metallothioneins and to study their pathophysiological role during hepatic IRP injury in lean livers and ethanol-induced steatotic livers as well as their potential to use MT gene expression as therapeutic target. Hence our specific experimental aims are: 1./2. Characterize postischemic induction of MTs and evaluate the potential protection against a Kupffer cell and neutrophil-induced oxidant stress and injury or its effects on micro-circulatory dysfunction during IRP injury in lean and steatotic livers. 3. Evaluate the induction of MTs during ischemic preconditioning and its overall impact on the protective effects of this procedure in lean and steatotic livers. 4. Study hepatoprotective mechanisms of MT induction in cultured mouse hepatocytes. The project will provide the preclinical basis for the development of a novel therapeutic strategy, which selectively targets the detrimental effects of an excessive inflammatory response during reperfusion without compromising the host defense function of neutrophils and Kupffer cells. Public Health Relevance: An inflammatory response with activation of Kupffer cells and neutrophils contribute to a wide variety of liver pathologies including hepatic ischemia-reperfusion injury (transplantation, tumor resections), alcoholic hepatitis, steatohepatitis and obstructive cholestasis. However, these leukocytes also fulfill a vital host defense function against invading microorganisms. Therefore, it is critical to identify and test novel therapeutic strategies, which selectively target the detrimental effects of an excessive inflammatory response without compromising the host defense function of neutrophils and Kupffer cells.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
Project #
Application #
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Radaeva, Svetlana
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Kansas
Schools of Medicine
Kansas City
United States
Zip Code
Weemhoff, James L; Woolbright, Benjamin L; Jenkins, Rosalind E et al. (2017) Plasma biomarkers to study mechanisms of liver injury in patients with hypoxic hepatitis. Liver Int 37:377-384
Ramachandran, Anup; Jaeschke, Hartmut (2017) PGAM5: a new player in immune-mediated liver injury. Gut 66:567-568
Woolbright, Benjamin L; Williams, C David; Ni, Hongmin et al. (2017) Microcystin-LR induced liver injury in mice and in primary human hepatocytes is caused by oncotic necrosis. Toxicon 125:99-109
Woolbright, Benjamin L; Jaeschke, Hartmut (2017) Role of the inflammasome in acetaminophen-induced liver injury and acute liver failure. J Hepatol 66:836-848
Woolbright, Benjamin L; Ding, Wen-Xing; Jaeschke, Hartmut (2017) Caspase inhibitors for the treatment of liver disease: friend or foe? Expert Rev Gastroenterol Hepatol 11:397-399
Ramachandran, Anup; Jaeschke, Hartmut (2017) Mechanisms of acetaminophen hepatotoxicity and their translation to the human pathophysiology. J Clin Transl Res 3:157-169
Woolbright, Benjamin L; Jaeschke, Hartmut (2016) Neurologic cues modulate immune-mediated liver injury and regeneration. Hepatology 63:1427-9
Du, Kuo; Jaeschke, Hartmut (2016) Liuweiwuling tablets protect against acetaminophen hepatotoxicity: What is the protective mechanism? World J Gastroenterol 22:3302-4
Jaeschke, Hartmut (2016) Acetaminophen hepatotoxicity and sterile inflammation: The mechanism of protection of Chlorogenic acid. Chem Biol Interact 243:148-9
Duan, Luqi; Davis, John S; Woolbright, Benjamin L et al. (2016) Differential susceptibility to acetaminophen-induced liver injury in sub-strains of C57BL/6 mice: 6N versus 6J. Food Chem Toxicol 98:107-118

Showing the most recent 10 out of 121 publications