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 focuses on a group of endogenous damage-associated molecular pattern (DAMP) molecules that emanate from the cell nucleus during infection and injury to initiate the activation of innate inflammatory responses. Our recent findings demonstrate that nuclear DAMPs are involved in neutrophil biology, namely neutrophil extracellular trap (NET) formation, in the setting of liver I/R. IL-33, novel member of the IL-1 family associated with chromatin in the nucleus, can act as a DAMP when released following liver I/R to stimulate NET formation. In addition to the presence of nuclear histones, we have also identified a novel requirement of intracellular high mobility group box-1 (HMGB1) protein in the ability of neutrophils to form NETs. Importantly, targeting NETs ameliorates the hepatic as well as systemic I/R-induced injury in mice. Thus, we propose that nuclear DAMPs (such as IL-33, histones, and HMGB1) mediate NET formation and subsequent organ injury following liver I/R. These mechanisms will also be validated in clinical outcomes of patients undergoing liver resection.
In Aim 1, we will determine the role of IL-33 in NET formation and inflammatory signaling during ischemic liver injury.
Aim 2 will identify the intracellular roles of HMGB1 in regulating neutrophil formation of NETs.
In Aim 3, we will establish the mechanisms of NET-mediated local and systemic organ injury following liver I/R. These studies will serve as a basis for developing both a more comprehensive understanding of how DAMPs mediate both harmful and adaptive responses during non-infectious inflammation, and should prove useful in the design of novel therapies, broadly applicable, to minimize tissue damage in a variety of clinical settings.

Public Health Relevance

This project will determine the mechanisms by which ischemic tissue of the liver utilize nuclear damage- associated molecular pattern molecules 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 #
2R01GM095566-06
Application #
9026878
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2010-12-01
Project End
2020-05-31
Budget Start
2016-07-15
Budget End
2017-05-31
Support Year
6
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Tohme, Samer; Yazdani, Hamza O; Liu, Yao et al. (2017) Hypoxia mediates mitochondrial biogenesis in hepatocellular carcinoma to promote tumor growth through HMGB1 and TLR9 interaction. Hepatology 66:182-197
Tohme, Samer; Kameneva, Marina V; Yazdani, Hamza O et al. (2017) Drag reducing polymers decrease hepatic injury and metastases after liver ischemia-reperfusion. Oncotarget 8:59854-59866
Tohme, Samer; Simmons, Richard L; Tsung, Allan (2017) Surgery for Cancer: A Trigger for Metastases. Cancer Res 77:1548-1552
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:
Liu, Shuai; Su, Xiaoli; Pan, Pinhua et al. (2016) Neutrophil extracellular traps are indirectly triggered by lipopolysaccharide and contribute to acute lung injury. Sci Rep 6:37252
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
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
Mcdonald, Kerry-Ann; Huang, Hai; Tohme, Samer et al. (2015) 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
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
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

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