Thorough understanding of the pathophysiology of liver ischemia reperfusion (I/R) is vital as it is commonly encountered clinically during elective liver surgical procedures, solid organ transplantation, trauma, and hypovolemic shock. Although the distal events involved in the inflammatory response resulting in liver damage after I/R injury has been well-studied, the proximal events dictating the propagation of the inflammatory response and further tissue damage is poorly understood. This proposal will study the mechanisms by which high mobility group box 1 (HMGB1), a nuclear protein involved in regulating interactions between DNA and transcription factors, can act as a key alarm molecule when released extracellularly during ischemic stress to active inflammatory responses. We propose that during ischemic stress, the parenchymal cells of the liver (hepatocyte), initially mobilize and release nuclear HMGB1. HMGB1 is then sensed by pattern recognition receptors, such as the family of toll-like receptors (TLR), expressed on neighboring immune cells to provide a critical link between tissue damage and activation and recruitment of the innate immune response.
In Aim 1, we will determine the signaling pathways governing the active release of HMGB1 from hepatocytes following oxidative stress. We will demonstrate the mechanisms by which calcium/ calmodulin-dependent protein kinase II control the acetylation status and subsequent release of HMGB1 through modification of histone deacetylase activity.
In Aim 2, we will show the key roles TLR4 play in HMGB1-mediated inflammation in vivo using a model of liver I/R.
In Aim 3, we will focus on hepatic dendritic cells as the primary immune cell type that responds to HMGB1 and regulates the inflammatory response to ischemic injury. These studies will serve as a basis for developing both a more comprehensive understanding of how innate immune cells are activated during liver I/R, and should prove useful in the design of novel therapies to minimize liver damage in a variety of surgical settings. Importantly, the mechanisms of inflammation mediated by HMGB1 release is likely common in a number of infectious and non-infectious inflammatory conditions found within the liver and the implications of this work likely extend to a variety of other ischemic conditions (e.g. myocardial infarction and cerebral ischemia).

Public Health Relevance

This project will determine the mechanisms by which ischemic tissue of the liver utilize a nuclear protein, HMGB1, to act as an alarm molecule to activate innate immune responses following liver ischemia and reperfusion injury. These studies will provide a more comprehensive understanding of how inflammatory pathways promote organ injury after ischemic insults and should prove useful in the design of novel therapies to minimize tissue damage and improve liver function in a variety of disease states.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM095566-04
Application #
8666554
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Somers, Scott D
Project Start
2011-09-15
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Al-Khafaji, Ahmed B; Tohme, Samer; Yazdani, Hamza Obaid et al. (2016) Superoxide induces Neutrophil Extracellular Trap Formation in a TLR-4 and NOX-dependent mechanism. Mol Med 22:
Tohme, Samer; Yazdani, Hamza O; Al-Khafaji, Ahmed B et al. (2016) Neutrophil Extracellular Traps Promote the Development and Progression of Liver Metastases after Surgical Stress. Cancer Res 76:1367-80
Huang, Hai; Tohme, Samer; Al-Khafaji, Ahmed B et al. (2015) Damage-associated molecular pattern-activated neutrophil extracellular trap exacerbates sterile inflammatory liver injury. Hepatology 62:600-14
Chen, Man; Liu, Yao; Varley, Patrick et al. (2015) High-Mobility Group Box 1 Promotes Hepatocellular Carcinoma Progression through miR-21-Mediated Matrix Metalloproteinase Activity. Cancer Res 75:1645-56
Liu, Yao; Yan, Wei; Tohme, Samer et al. (2015) Hypoxia induced HMGB1 and mitochondrial DNA interactions mediate tumor growth in hepatocellular carcinoma through Toll-like receptor 9. J Hepatol 63:114-21
Kang, Rui; Zhang, Qiuhong; Hou, Wen et al. (2014) Intracellular Hmgb1 inhibits inflammatory nucleosome release and limits acute pancreatitis in mice. Gastroenterology 146:1097-107
Huang, Hai; Nace, Gary W; McDonald, Kerry-Ann et al. (2014) Hepatocyte-specific high-mobility group box 1 deletion worsens the injury in liver ischemia/reperfusion: a role for intracellular high-mobility group box 1 in cellular protection. Hepatology 59:1984-97
Mcdonald, Kerry-Ann; Huang, Hai; Tohme, Samer et al. (2014) Toll-like receptor 4 (TLR4) antagonist eritoran tetrasodium attenuates liver ischemia and reperfusion injury through inhibition of high-mobility group box protein B1 (HMGB1) signaling. Mol Med 20:639-48
Nace, Gary W; Huang, Hai; Klune, John R et al. (2013) Cellular-specific role of toll-like receptor 4 in hepatic ischemia-reperfusion injury in mice. Hepatology 58:374-87
Czaja, Mark J; Ding, Wen-Xing; Donohue Jr, Terrence M et al. (2013) Functions of autophagy in normal and diseased liver. Autophagy 9:1131-58

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