lschemia/reperfusion (I/R) insult remains one of the major limitations of orthotopic liver transplantation (OLT). This proposal is built upon the insights gained from our studies on a novel approach of inducing heme oxygenase-1 (HO-1) expression in OLTs. We hypothesize that: (i) HO-I facilitates a systemic mileu, which via STAT6 pathway leads to emergence of a dominant """"""""cytoprotectlve"""""""" type-2 T cell subset; (ii) HO-1 depresses apoptotic machinery and triggers type-2 anti-apoptotic cytoprotactive mechanisms; (iii) hyaluronic acid (HA) provides a """"""""danger"""""""" signal to activate toll-like receptor 4 (TLR 4) complex on Kupffer cells; HO-1 - TLR 4 cross-talk prevents l/R insult by keeping Kupffer cetl activation in check. We propose following specific aims: (1). To evaluate local vs. systemic ceil requirements for HO-1-facilitated cytoprotection; By using HO-1 Tg mice, we will determine impact of local (endothelial/parenchymal) vs. systemic (lymphocyte) HO-1 expression. We will analyze which hepatic components vs. spleen T cell subsets are instrumental in HO-1 effects. The role of STAT6 in the emergence of a dominant HO-1-dependent cytoprotective type-2 T cell will be assessed. (2). To dissect apoptotic/anti-apoptotic pathways in the mechanism of HO-1-facilitated cytoprotection: We plan to determine the molecular basis of HO-1 mediated cytoprotection in OLT recipients and in primary mouse hepatocyte cultures upon the death signaling machinery (TNF/FasL), and apoptotic stimuli (ROS). This will include activation of caspases, cytochrome c release, and expression of anti-/pro-apoptotic genes. We will analyze whether HO-1-mediated depression of apoptotic machinery in hepatocytes and upregulation of endothelial anti-apoptotic molecules represents local hepatic or systemic T cell-dependent feature. (3). To explore cross-talk between HO-1 and TLR 4 complex - I/R injury a case for innate immunity? We will study how HA, shed from damaged sinusoidai endothelial cells, interacts with Kupffer cells, to what extent HA triggers expression/activation of Kupffer ceils in TLR 4 mutant/deficient vs. WT mice. The ability of sHA to affect hepatic I/R insult in TLR 4 mutant/TLR 4 KO mice will be probed. We will analyze by which mechanism depression of HO activity affects innate immunity balance, and triggers phenotypic/functional TLR4 activation.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Doo, Edward
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University of California Los Angeles
Schools of Medicine
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Kageyama, Shoichi; Hirao, Hirofumi; Nakamura, Kojiro et al. (2018) Recipient HO-1 inducibility is essential for posttransplant hepatic HO-1 expression and graft protection: From bench-to-bedside. Am J Transplant :
Zhang, Min; Nakamura, Kojiro; Kageyama, Shoichi et al. (2018) Myeloid HO-1 modulates macrophage polarization and protects against ischemia-reperfusion injury. JCI Insight 3:
Kageyama, Shoichi; Nakamura, Kojiro; Ke, Bibo et al. (2018) Serelaxin induces Notch1 signaling and alleviates hepatocellular damage in orthotopic liver transplantation. Am J Transplant 18:1755-1763
Nakamura, Kojiro; Kageyama, Shoichi; Yue, Shi et al. (2018) Heme oxygenase-1 regulates sirtuin-1-autophagy pathway in liver transplantation: From mouse to human. Am J Transplant 18:1110-1121
Lu, Ling; Yue, Shi; Jiang, Longfeng et al. (2018) Myeloid Notch1 deficiency activates the RhoA/ROCK pathway and aggravates hepatocellular damage in mouse ischemic livers. Hepatology 67:1041-1055
Kageyama, Shoichi; Nakamura, Kojiro; Fujii, Takehiro et al. (2018) Recombinant relaxin protects liver transplants from ischemia damage by hepatocyte glucocorticoid receptor: From bench-to-bedside. Hepatology 68:258-273
Nakamura, Kojiro; Kageyama, Shoichi; Ke, Bibo et al. (2017) Sirtuin 1 attenuates inflammation and hepatocellular damage in liver transplant ischemia/Reperfusion: From mouse to human. Liver Transpl 23:1282-1293
Zhang, C; Zhang, Y; Liu, Y et al. (2017) A Soluble Form of P Selectin Glycoprotein Ligand 1 Requires Signaling by Nuclear Factor Erythroid 2-Related Factor 2 to Protect Liver Transplant Endothelial Cells Against Ischemia-Reperfusion Injury. Am J Transplant 17:1462-1475
Nakamura, Kojiro; Zhang, Min; Kageyama, Shoichi et al. (2017) Macrophage heme oxygenase-1-SIRT1-p53 axis regulates sterile inflammation in liver ischemia-reperfusion injury. J Hepatol 67:1232-1242
Liu, Yuanxing; Ji, Haofeng; Zhang, Yu et al. (2015) Negative CD4?+?TIM-3 signaling confers resistance against cold preservation damage in mouse liver transplantation. Am J Transplant 15:954-964

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