Advancements in immunosuppressive drugs, surgical techniques, and postoperative care have significantly improved outcomes of liver transplantation;however, cold preservation-associated ischemia/reperfusion (I/R) injury remains a major problem complicating posttransplant care and subsequent long-term transplant outcomes. Further, the recent organ shortage demands to expand the donor pool, and the use of liver grafts from marginal donors possibly augments I/R injury. Carbon monoxide (CO), an endogenous byproduct of heme, has lately received notable attention as a regulatory molecule in cellular and biological processes. During the last 3 years, we have evaluated the cytoprotective function of CO and obtained encouraging results showing that exogenous inhaled CO provides benefits against transplant-induced hepatic I/R injury. We hypothesize that CO protects liver grafts from hepatic I/R injury via the regulation of proinflammatory responses by directly inhibiting Kupffer cell activation and by improving sinusoidal circulation. We will pursue two specific aims to explore the clinical applicability, efficacy, and mechanisms of protection of low dose inhaled CO in ameliorating liver damage due to transplant preservation injury.
AIM I : TO OPTIMIZE INHALED CO DELIVERY TO INHIBIT LIVER I/R INJURY. We will fully explore the regulatory effects of inhaled CO delivered in a clinically applicable manner to ameliorate hepatic I/R injury. Optimization of the delivery protocol will be established by administering CO as a brief inhalation therapy during the peritransplant period. To maximize CO efficacy, we will study effects obtained with donor and/or recipient treatment with CO. The potential adverse consequences of CO inhalation will also be investigated.
AIM II : TO IDENTIFY THE MECHANISMS OF CO-MEDIATED PROTECTION OF LIVER GRAFTS. We will determine Kupffer cells as CO's direct target for antiproinflammatory function. Molecular mechanisms of CO- mediated antiinflammatory protection via the MAPK signaling pathways will be analyzed in isolated cell population. We will determine the mechanism of CO-mediated SEC protection and hepatic sinusoidal circulation via the inhibition of stellate cell activation and endothelin (ET) system. Our long-term goal in this proposal is to harness the benefit of CO pathway to improve early liver graft function and minimize the morbidity associated with severe preservation injury by fully exploring the regulatory mechanisms of CO.

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 Pittsburgh
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Kimura, Shoko; Ozaki, Kikumi S; Ueki, Shinya et al. (2016) Contribution of alloantigens to hepatic ischemia/reperfusion injury: Roles of natural killer cells and innate immune recognition of nonself. Liver Transpl 22:80-90
Zhang, Matthew; Ueki, Shinya; Kimura, Shoko et al. (2013) Roles of dendritic cells in murine hepatic warm and liver transplantation-induced cold ischemia/reperfusion injury. Hepatology 57:1585-96
Klune, John R; Dhupar, Rajeev; Kimura, Shoko et al. (2012) Interferon regulatory factor-2 is protective against hepatic ischemia-reperfusion injury. Am J Physiol Gastrointest Liver Physiol 303:G666-73
Ozaki, Kikumi S; Kimura, Shoko; Nalesnik, Michael A et al. (2012) The loss of renal dendritic cells and activation of host adaptive immunity are long-term effects of ischemia/reperfusion injury following syngeneic kidney transplantation. Kidney Int 81:1015-25
Dangi, Anil; Sumpter, Tina L; Kimura, Shoko et al. (2012) Selective expansion of allogeneic regulatory T cells by hepatic stellate cells: role of endotoxin and implications for allograft tolerance. J Immunol 188:3667-77
Ozaki, Kikumi S; Yoshida, Junichi; Ueki, Shinya et al. (2012) Carbon monoxide inhibits apoptosis during cold storage and protects kidney grafts donated after cardiac death. Transpl Int 25:107-17
Ozaki, Kikumi S; Kimura, Shoko; Murase, Noriko (2012) Use of carbon monoxide in minimizing ischemia/reperfusion injury in transplantation. Transplant Rev (Orlando) 26:125-39
Ueki, Shinya; Castellaneta, Antonino; Yoshida, Osamu et al. (2011) Hepatic B7 homolog 1 expression is essential for controlling cold ischemia/reperfusion injury after mouse liver transplantation. Hepatology 54:216-28
Lee, Lung-Yi; Kaizu, Takashi; Toyokawa, Hideyoshi et al. (2011) Carbon monoxide induces hypothermia tolerance in Kupffer cells and attenuates liver ischemia/reperfusion injury in rats. Liver Transpl 17:1457-66
Yoshida, J; Ozaki, K S; Nalesnik, M A et al. (2010) Ex vivo application of carbon monoxide in UW solution prevents transplant-induced renal ischemia/reperfusion injury in pigs. Am J Transplant 10:763-72

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