肝穿刺切片檢查(liver biopsy)是現行唯一肝臟移植急性排斥的確診方式，然而肝穿刺術是一種高度侵入性且極為疼痛的診斷方式，同時可能會導致出血和感染等併發症，更甚之會導致部份肝移植體的流失。因此發展非侵入性且可行的診斷方式，對於肝移植急性排斥的早期預測與診斷是相當重要的。急性排斥會造成活性氧化物(ROS)和抗氧化物(antioxidant)的失衡，過多的ROS的累積會導致氧化壓力(oxidative stress)的發生，當氧化壓力發生時將會誘發一氧化氮(NO)的生成。此研究報告的目的在於探討肝移植急性排斥造成氧化壓力的分子機制，及NO與其氧化物作為肝移植急性排斥中，非侵入性診斷的潛力。我們藉由大鼠原位肝臟移植術的動物模式，探討在急性排斥中 MAPK和Nrf2調控的分子機制。實驗結果顯示肝移植急性排斥模式大鼠(DA-LEW)，在術後第7天的血清AST，ALT，和丙二醛(MDA)顯著高於正常鼠(LEW)和移植控制組大鼠(LEW-LEW)。DA-LEW肝移植體中表現的促發炎細胞因子(proinflammatory cytokines)，iNOS，COX-2顯著較高。而p-ERK和p-38 MAPK表現顯著降低，顯示ERK和p38 MAPK的活性降低導致Nrf2調控抗氧化基因的表現能力降低。並且Bax和活化的caspase-3在急性排斥的肝臟中表現增加，顯示可能與ROS所誘發的細胞凋亡有關。此外，在急性排斥模式大鼠(DA-LEW)呼氣所含的NO，及其血清總NO2-和NO3-顯著高於正常(naive LEW)和移植控制組大鼠(LEW-LEW)，但在抗排斥藥物環孢菌素(cyclosporin A)的施予後，血清總NO2-和NO3-降至與正常和移植控制組大鼠相當的水準，結果顯示呼氣所含NO及血清總NO2-和NO3-具有成為肝移植急性排斥中，非侵入性診斷的潛力。總結，這份研究報告提出在肝移植急性排斥中，MAPK和Nrf2調控的分子機制與急性排斥有關，及呼氣所含NO及血清總NO2-和NO3-有潛力作為肝移植急性排斥的預測和非侵入性診斷方法。

Liver biopsy is currently the only means of definite diagnosis of acute rejection (AR), while it is invasive and painful, resulting in several complications such as bleeding, infection, and rarely, graft loss. Therefore, the development of noninvasive and feasible diagnosis tool is important for early prediction and diagnosis of AR. AR leads to imbalance of reactive oxygen species (ROS) generation and natural antioxidant defense, and excessive ROS formation induces oxidative stress, which triggers free radical nitric oxide (NO) synthesis. This study aimed to explore molecular mechanisms of AR and diagnostic potential of NO and its oxidation products in liver transplantation. Using a rat orthotopic liver transplantation (OLT) model, we explored mitogen-activated protein kinase (MAPK) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-mediated molecular mechanisms of AR. LEW rats with AR (DA-LEW OLT at day 7) showed significantly higher levels of aspartate transaminase (AST), alanine transaminase (ALT) and lipid peroxidation product (malondialdehyde: MDA) as compared with naive LEW and syngeneic LEW-LEW OLT rats. Proinflammatory cytokines, induced nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were significantly elevated in DA-LEW OLT livers. Levels of phosphorylated extracellular signal-regulated kinase (p-ERK) and phosphorylated p38 MAPK (p-38 MAPK) were significantly downregulated in DA-LEW OLT livers, resulting in the inactivation of Nrf2-mediated antioxidant defense. Induction of Bax and cleaved caspase-3 suggested ROS-mediated apoptosis in DA-LEW OLT livers. Exhaled breath NO as well as serum nitrite and nitrate (NO2- and NO3-; NOx) were significantly increased in DA-LEW, but not in LEW-LEW OLT rats. Cyclosporine A clearly suppressed the induction of NOx, suggesting the diagnostic potential of NO and its oxidation products in AR. In summary, we present MAPK and Nrf2-mediated molecular mechanisms of AR and a potential of serum NOx and exhaled breath NO for prediction and diagnosis of AR.

論文審定書_i
公開授權書_ii
摘要_iii
Abstract_iv
Content_v
Introduction_1
Materials and Methods_5
Results_9
Discussion_12
Figures and Legends_15
Tables_27
Supplemental Figure_30
References_31

[1] T. E. Starzl, T. L. Marchioro, K. N. Vonkaulla, G. Hermann, R. S. Brittain, and W. R. Waddell, “Homotransplantation of the Liver in Humans.,” Surg. Gynecol. Obstet., vol. 117, pp. 659–76, Dec. 1963.
[2] C. L. Chen, A. M. Concejero, and Y. F. Cheng, “More than a quarter of a century of liver transplantation in Kaohsiung Chang Gung Memorial Hospital.,” Clinical transplants. pp. 213–221, 2011.
[3] A. Jain, J. Reyes, R. Kashyap, S. F. Dodson, A. J. Demetris, K. Ruppert, K. Abu-Elmagd, W. Marsh, J. Madariaga, G. Mazariegos, D. Geller, C. A. Bonham, T. Gayowski, T. Cacciarelli, P. Fontes, T. E. Starzl, and J. J. Fung, “Long-term survival after liver transplantation in 4,000 consecutive patients at a single center.,” Ann. Surg., vol. 232, no. 4, pp. 490–500, 2000.
[4] F. Y. Yao, L. Ferrell, N. M. Bass, J. J. Watson, P. Bacchetti, A. Venook, N. L. Ascher, and J. P. Roberts, “Liver transplantation for hepatocellular carcinoma: Expansion of the tumor size limits does not adversely impact survival.,” Hepatology, vol. 33, no. 6, pp. 1394–1403, 2001.
[5] J. F. Lock, E. Schwabauer, P. Martus, N. Videv, J. Pratschke, M. Malinowski, P. Neuhaus, and M. Stockmann, “Early diagnosis of primary nonfunction and indication for reoperation after liver transplantation.,” Liver Transpl., vol. 16, no. 2, pp. 172–80, Feb. 2010.
[6] L. Lladó, J. Fabregat, J. Castellote, E. Ramos, J. Torras, R. Jorba, F. Garcia-Borobia, J. Busquets, J. Figueras, and A. Rafecas, “Management of portal vein thrombosis in liver transplantation: influence on morbidity and mortality.,” Clin. Transplant., vol. 21, no. 6, pp. 716–21, 2007.
[7] A. Annamalai, I. Kim, V. Sundaram, and A. Klein, “Incidence and risk factors of deep vein thrombosis after liver transplantation.,” Transplant. Proc., vol. 46, no. 10, pp. 3564–9, Dec. 2014.
[8] V. Kirimlioglu, F. Tatli, V. Ince, C. Aydin, V. Ersan, C. Ara, M. Aladag, R. Kutlu, H. Kirimlioglu, and S. Yilmaz, “Biliary complications in 106 consecutive duct-to-duct biliary reconstruction in right-lobe living donor liver transplantation performed in 1 year in a single center: a new surgical technique.,” Transplant. Proc., vol. 43, no. 3, pp. 917–20, Apr. 2011.
[9] T. Hampe, A. Dogan, J. Encke, A. Mehrabi, P. Schemmer, J. Schmidt, A. Stiehl, and P. Sauer, “Biliary complications after liver transplantation,” Clin. Transplant., vol. 20, no. SUPPL. 17, pp. 93–96, Apr. 2006.
[10] A. Shaked, R. M. Ghobrial, R. M. Merion, T. H. Shearon, J. C. Emond, J. H. Fair, R. A. Fisher, L. M. Kulik, T. L. Pruett, and N. A. Terrault, “Incidence and severity of acute cellular rejection in recipients undergoing adult living donor or deceased donor liver transplantation.,” Am. J. Transplant, vol. 9, no. 2, pp. 301–308, 2009.
[11] A. J. Demetris, K. P. Batts, A. P. Dhillon, L. Ferrell, J. Fung, S. a. Geller, J. Hart, P. Hayry, W. J. Hofmann, S. Hubscher, J. Kemnitz, G. Koukoulis, R. G. Lee, K. J. Lewin, J. Ludwig, R. S. Markin, L. M. Petrovic, M. James Phillips, B. Portmann, J. Rakela, P. Randhawa, F. P. Reinholt, M. Reynés, M. Robert, H. Schlitt, K. Solez, D. Snover, E. Taskinen, S. N. Thung, G. Weldon Tillery, R. H. Wiesner, D. G. Derek Wight, J. W. Williams, and H. Yamabe, “Banff schema for grading liver allograft rejection: An international consensus document.,” Hepatology, vol. 25, no. 3, pp. 658–663, Mar. 1997.
[12] S. Hübscher, “Transplantation Pathology.,” Semin. Liver Dis., vol. 29, no. 01, pp. 074–090, Feb. 2009.
[13] E. Ishii, A. Shimizu, N. Kuwahara, T. Arai, M. Kataoka, K. Wakamatsu, A. Ishikawa, S. Nagasaka, and Y. Fukuda, “Lymphangiogenesis associated with acute cellular rejection in rat liver transplantation.,” Transplant. Proc., vol. 42, no. 10, pp. 4282–4285, Dec. 2010.
[14] Y. Kishi, Y. Sugawara, S. Tamura, J. Kaneko, Y. Matsui, and M. Makuuchi, “Histologic eosinophilia as an aid to diagnose acute cellular rejection after living donor liver transplantation.,” Clin. Transplant., vol. 21, no. 2, pp. 214–8, 2007.
[15] A. Dankof, M. Schmeding, L. Morawietz, R. Günther, M. G. Krukemeyer, B. Rudolph, M. Koch, V. Krenn, and U. Neumann, “Portal capillary C4d deposits and increased infiltration by macrophages indicate humorally mediated mechanisms in acute cellular liver allograft rejection.,” Virchows Arch., vol. 447, no. 1, pp. 87–93, Jul. 2005.
[16] L. H. Gao, S. S. Zheng, Y. F. Zhu, Y. L. Wan, Y. L. Wang, G. Q. Wei, S. K. Qian, S. Q. Qian, and W. J. Jiang, “A rat model of chronic allograft liver rejection.,” Transplant. Proc., vol. 37, no. 5, pp. 2327–32, Jun. 2005.
[17] S. G. Hübscher, “What is the long-term outcome of the liver allograft?,” J. Hepatol., vol. 55, no. 3, pp. 702–17, Sep. 2011.
[18] A. Demetris, D. Adams, C. Bellamy, K. Blakolmer, A. Clouston, a P. Dhillon, J. Fung, A. Gouw, B. Gustafsson, H. Haga, D. Harrison, J. Hart, S. Hubscher, R. Jaffe, U. Khettry, C. Lassman, K. Lewin, O. Martinez, Y. Nakazawa, D. Neil, O. Pappo, M. Parizhskaya, P. Randhawa, S. Rasoul-Rockenschaub, F. Reinholt, M. Reynes, M. Robert, A. Tsamandas, I. Wanless, R. Wiesner, A. Wernerson, F. Wrba, J. Wyatt, and H. Yamabe, “Update of the International Banff Schema for Liver Allograft Rejection: working recommendations for the histopathologic staging and reporting of chronic rejection. An International Panel.,” Hepatology, vol. 31, no. 3, pp. 792–799, Mar. 2000.
[19] C. L. Sánchez, O. Len, J. Gavalda, I. Bilbao, L. Castells, M. A. Gelabert, H. Allende, and A. Pahissa, “Liver biopsy-related infection in liver transplant recipients: A current matter of concern?,” Liver Transpl., vol. 20, no. 5, pp. 552–6, May 2014.
[20] R. J. Firpi, M. F. Abdelmalek, C. Soldevila-Pico, R. Cabrera, J. J. Shuster, D. Theriaque, A. I. Reed, A. W. Hemming, C. Liu, J. M. Crawford, and D. R. Nelson, “One-year protocol liver biopsy can stratify fibrosis progression in liver transplant recipients with recurrent hepatitis C infection.,” Liver Transpl., vol. 10, no. 10, pp. 1240–7, Oct. 2004.
[21] S. M. Kim, H. W. Kim, E. K. Lee, S. K. Park, D. J. Han, and S. B. Kim, “Usefulness of Liver Biopsy in Anti-Hepatitis C Virus Antibody-Positive and Hepatitis C Virus RNA-Negative Kidney Transplant Recipients.,” Transplantation, vol. 96, no. 1, pp. 85–90, Jul. 2013.
[22] A. Minguela, A. M. García-Alonso, L. Marín, A. Torio, F. Sánchez-Bueno, J. Bermejo, P. Parrilla, and M. R. Alvarez-López, “Evidence of CD28 upregulation in peripheral T cells before liver transplant acute rejection.,” Transplant. Proc., vol. 29, no. 1–2, pp. 499–500, 1997.
[23] A. Minguela, M. Miras, J. Bermejo, F. Sánchez-Bueno, M. R. López-Alvarez, M. R. Moya-Quiles, M. Muro, J. Ontañón, A. M. Garía-Alonso, P. Parrilla, and M. R. Alvarez-López, “HBV and HCV infections and acute rejection differentially modulate CD95 and CD28 expression on peripheral blood lymphocytes after liver transplantation.,” Hum. Immunol., vol. 67, no. 11, pp. 884–93, Nov. 2006.
[24] E. Boleslawski, S. BenOthman, S. Grabar, L. Correia, P. Podevin, S. Chouzenoux, O. Soubrane, Y. Calmus, and F. Conti, “CD25, CD28 and CD38 expression in peripheral blood lymphocytes as a tool to predict acute rejection after liver transplantation.,” Clin. Transplant., vol. 22, no. 4, pp. 494–501, Jan. 2008.
[25] J. D. Perkins, D. L. Nelson, J. Rakela, P. M. Grambsch, and R. A. Krom, “Soluble interleukin-2 receptor level as an indicator of liver allograft rejection.,” Transplantation, vol. 47, no. 1, pp. 77–81, Jan. 1989.
[26] D. H. Adams, L. Wang, S. G. Hubscher, E. Elias, and J. M. Neuberger, “Soluble interleukin-2 receptors in serum and bile of liver transplant recipients.,” Lancet, vol. 1, no. 8636, pp. 469–71, Mar. 1989.
[27] M. Hazzan, M. Labalette, C. Noel, G. Lelievre, and J. P. Dessaint, “Recall response to cytomegalovirus in allograft recipients: mobilization of CD57+, CD28+ cells before expansion of CD57+, CD28- cells within the CD8+ T lymphocyte compartment.,” Transplantation, vol. 63, no. 5, pp. 693–8, Mar. 1997.
[28] K. P. Platz, A. R. Mueller, R. Rossaint, T. Steinmüller, H. P. Lemmens, H. Lobeck, and P. Neuhaus, “Cytokine pattern during rejection and infection after liver transplantation--improvements in postoperative monitoring?,” Transplantation, vol. 62, no. 10, pp. 1441–50, Nov. 1996.
[29] R. J. Kowalski, D. R. Post, R. B. Mannon, A. Sebastian, H. I. Wright, G. Sigle, J. Burdick, K. A. Elmagd, A. Zeevi, M. Lopez-Cepero, J. A. Daller, H. A. Gritsch, E. F. Reed, J. Jonsson, D. Hawkins, and J. A. Britz, “Assessing relative risks of infection and rejection: a meta-analysis using an immune function assay.,” Transplantation, vol. 82, no. 5, pp. 663–8, Sep. 2006.
[30] M. A. Pappolla, R. A. Omar, K. S. Kim, and N. K. Robakis, “Immunohistochemical evidence of oxidative [corrected] stress in Alzheimer’s disease.,” Am. J. Pathol., vol. 140, no. 3, pp. 621–8, Mar. 1992.
[31] M. E. Götz, G. Künig, P. Riederer, and M. B. Youdim, “Oxidative stress: free radical production in neural degeneration.,” Pharmacol. Ther., vol. 63, no. 1, pp. 37–122, Jan. 1994.
[32] J. W. Baynes, “Role of oxidative stress in development of complications in diabetes.,” Diabetes, vol. 40, no. 4, pp. 405–12, Apr. 1991.
[33] A. G. Ziady and J. Hansen, “Redox balance in cystic fibrosis.,” Int. J. Biochem. Cell Biol., vol. 52, pp. 113–23, Jul. 2014.
[34] M. G. Simic, “DNA markers of oxidative processes in vivo: relevance to carcinogenesis and anticarcinogenesis.,” Cancer Res., vol. 54, no. 7 Suppl, p. 1918s–1923s, Apr. 1994.
[35] G. M. Cunningham, M. G. Roman, L. C. Flores, G. B. Hubbard, A. B. Salmon, Y. Zhang, J. Gelfond, and Y. Ikeno, “The paradoxical role of thioredoxin on oxidative stress and aging.,” Arch. Biochem. Biophys., vol. 576, pp. 32–38, Jun. 2015.
[36] V. I. Lushchak, “Free radicals, reactive oxygen species, oxidative stress and its classification.,” Chem. Biol. Interact., vol. 224, pp. 164–175, Dec. 2014.
[37] M. B. Hampton and S. Orrenius, “Redox regulation of apoptotic cell death.,” Biofactors, vol. 8, no. 1–2, pp. 1–5, Jan. 1998.
[38] B. Poljsak, D. Šuput, and I. Milisav, “Achieving the balance between ROS and antioxidants: When to use the synthetic antioxidants.,” Oxid. Med. Cell. Longev., vol. 2013, 2013.
[39] M. A. Aon, S. Cortassa, F. G. Akar, and B. O’Rourke, “Mitochondrial criticality: A new concept at the turning point of life or death.,” Biochimica et Biophysica Acta - Molecular Basis of Disease, vol. 1762, no. 2. pp. 232–240, 2006.
[40] D. Del Rio, A. J. Stewart, and N. Pellegrini, “A review of recent studies on malondialdehyde as toxic molecule and biological marker of oxidative stress.,” Nutr. Metab. Cardiovasc. Dis., vol. 15, no. 4, pp. 316–328, 2005.
[41] P. Czubkowski, P. Socha, and J. Pawlowska, “Oxidative stress in liver transplant recipients.,” Ann. Transplant., vol. 16, no. 1, pp. 99–108, 2011.
[42] Y. F. Tsai, F. C. Liu, W. C. Sung, C. C. Lin, P. C. H. Chung, W. C. Lee, and H. P. Yu, “Ischemic Reperfusion Injury–Induced Oxidative Stress and Pro-inflammatory Mediators in Liver Transplantation Recipients.,” Transplant. Proc., vol. 46, no. 4, pp. 1082–1086, May 2014.
[43] A. al Khader, M. al Sulaiman, P. N. Kishore, C. Morais, and M. Tariq, “Quinacrine attenuates cyclosporine-induced nephrotoxicity in rats.,” Transplantation, vol. 62, no. 4, pp. 427–435, 1996.
[44] Z. Mostafavi-pour, F. Zal, A. Monabati, and M. Vessal, “Protective effects of a combination of quercetin and vitamin E against cyclosporine A-induced oxidative stress and hepatotoxicity in rats.,” Hepatol. Res., vol. 38, no. 4, pp. 385–392, 2008.
[45] J. Cheng, L. Zhou, J. W. Jiang, Y. S. Qin, H. Y. Xie, X. W. Feng, F. Gao, and S. S. Zheng, “Proteomic analysis of differentially expressed proteins in rat liver allografts developed acute rejection.,” Eur. Surg. Res., vol. 44, no. 1, pp. 43–51, Jan. 2010.
[46] Y. Nagakawa, G. M. Williams, Q. Zheng, A. Tsuchida, T. Aoki, R. A. Montgomery, A. S. Klein, and Z. Sun, “Oxidative mitochondrial DNA damage and deletion in hepatocytes of rejecting liver allografts in rats: Role of TNF-α.,” Hepatology, vol. 42, no. 1, pp. 208–215, 2005.
[47] D. Martin, A. I. Rojo, M. Salinas, R. Diaz, G. Gallardo, J. Alam, C. M. Ruiz De Galarreta, and A. Cuadrado, “Regulation of Heme Oxygenase-1 Expression through the Phosphatidylinositol 3-Kinase/Akt Pathway and the Nrf2 Transcription Factor in Response to the Antioxidant Phytochemical Carnosol.,” J. Biol. Chem., vol. 279, no. 10, pp. 8919–8929, 2004.
[48] R. Venugopal and A. K. Jaiswal, “Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase1 gene.,” Proc. Natl. Acad. Sci. U. S. A., vol. 93, no. 25, pp. 14960–14965, 1996.
[49] S. A. Reisman, R. L. Yeager, M. Yamamoto, and C. D. Klaassen, “Increased Nrf2 activation in livers from keap1-knockdown mice Increases expression of cytoprotective genes that detoxify electrophiles more than those that detoxify reactive oxygen species.,” Toxicol. Sci., vol. 108, no. 1, pp. 35–47, 2009.
[50] T. Rangasamy, C. Y. Cho, R. K. Thimmulappa, L. Zhen, S. S. Srisuma, T. W. Kensler, M. Yamamoto, I. Petrache, R. M. Tuder, and S. Biswal, “Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice.,” J. Clin. Invest., vol. 114, no. 9, pp. 1248–1259, 2004.
[51] H. Y. Cho, S. P. Reddy, A. Debiase, M. Yamamoto, and S. R. Kleeberger, “Gene expression profiling of NRF2-mediated protection against oxidative injury.,” Free Radic. Biol. Med., vol. 38, no. 3, pp. 325–343, 2005.
[52] Y. S. Keum and B. Y. Choi, “Molecular and chemical regulation of the keap1-Nrf2 signaling pathway.,” Molecules, vol. 19, no. 7, pp. 10074–10089, 2014.
[53] S. Davinelli, D. C. Willcox, and G. Scapagnini, “Extending healthy ageing: nutrient sensitive pathway and centenarian population.,” Immun. Ageing, vol. 9, p. 9, Jan. 2012.
[54] B. Ke, X. Da Shen, Y. Zhang, H. Ji, F. Gao, S. Yue, N. Kamo, Y. Zhai, M. Yamamoto, R. W. Busuttil, and J. W. Kupiec-Weglinski, “KEAP1-NRF2 complex in ischemia-induced hepatocellular damage of mouse liver transplants.,” J. Hepatol., vol. 59, no. 6, pp. 1200–1207, 2013.
[55] B. F. Peake, C. K. Nicholson, J. P. Lambert, R. L. Hood, H. Amin, S. Amin, and J. W. Calvert, “Hydrogen sulfide preconditions the db/db diabetic mouse heart against ischemia-reperfusion injury by activating Nrf2 signaling in an Erk-dependent manner.,” Am. J. Physiol. Heart Circ. Physiol., vol. 304, no. 9, pp. H1215–24, 2013.
[56] H. Y. Yoon, N. I. Kang, H. K. Lee, K. Y. Jang, J. W. Park, and B. H. Park, “Sulforaphane protects kidneys against ischemia-reperfusion injury through induction of the Nrf2-dependent phase 2 enzyme.,” Biochem. Pharmacol., vol. 75, no. 11, pp. 2214–2223, 2008.
[57] W. Wu, Q. Qiu, H. Wang, S. A. Whitman, D. Fang, F. Lian, and D. D. Zhang, “Nrf2 is crucial to graft survival in a rodent model of heart transplantation.,” Oxid. Med. Cell. Longev., vol. 2013, 2013.
[58] M. Hori, M. Kita, S. Torihashi, S. Miyamoto, K. J. Won, K. Sato, H. Ozaki, and H. Karaki, “Upregulation of iNOS by COX-2 in muscularis resident macrophage of rat intestine stimulated with LPS.,” Am. J. Physiol. Gastrointest. Liver Physiol., vol. 280, no. 5, pp. G930–8, May 2001.
[59] R. Patel, M. G. Attur, M. Dave, S. B. Abramson, and A. R. Amin, “Regulation of cytosolic COX-2 and prostaglandin E2 production by nitric oxide in activated murine macrophages.,” J. Immunol., vol. 162, no. 7, pp. 4191–7, Apr. 1999.
[60] L. E. Prestes-Carneiro, M. T. Shio, P. D. Fernandes, and S. Jancar, “Cross-regulation of iNOS and COX-2 by its products in murine macrophages under stress conditions.,” Cell. Physiol. Biochem., vol. 20, no. 5, pp. 283–92, Jan. 2007.
[61] Y. Yamaguchi, K. Okabe, F. Matsumura, E. Akizuki, T. Matsuda, H. Ohshiro, J. Liang, S. Yamada, K. Mori, and M. Ogawa, “Peroxynitrite formation during rat hepatic allograft rejection.,” Hepatology, vol. 29, no. 3, pp. 777–784, 1999.
[62] G. Y. Wang, W. Meng, B. Ji, X. H. Du, and J. Zhao, “Expression of inducible nitric oxide synthase in transplanted rat liver and its inhibitory effect.,” Hepatobiliary & pancreatic diseases international : HBPD INT, vol. 4, no. 3. pp. 360–363, 2005.
[63] T. J. Martelius, H. Wolff, C. A. Bruggeman, K. A. Höckerstedt, and I. T. Lautenschlager, “Induction of cyclo-oxygenase-2 by acute liver allograft rejection and cytomegalovirus infection in the rat.,” Transpl. Int., vol. 15, no. 12, pp. 610–4, Dec. 2002.
[64] V. N. Thorat, A. N. Suryakar, P. Nailk, and B. M. Tiwale, “Nitric oxide: A useful indicator in acute allograft rejection after liver transplantation.,” Indian J. Clin. Biochem., vol. 24, no. 1, pp. 105–107, 2009.
[65] E. Fábrega, F. Casafont, J. de la Pena, J. R. Berrazueta, G. de las Heras, J. A. Amado, and F. Pons-Romero, “Nitric oxide production in hepatic cell rejection of liver transplant patients.,” Transplant. Proc., vol. 29, no. 1–2, pp. 505–506, 1997.
[66] J. M. Langrehr, N. Murase, P. M. Markus, X. Cal, P. Neuhaus, W. Schraut, R. L. Simmons, and R. A. Hoffman, “Nitric oxide production in host-versus-graft and graft-versus-host reactions in the rat.,” J. Clin. Invest., vol. 90, no. 2, pp. 679–683, 1992.
[67] C. LaForce, E. Brooks, N. Herje, P. Dorinsky, and K. Rickard, “Impact of exhaled nitric oxide measurements on treatment decisions in an asthma specialty clinic.,” Annals of Allergy, Asthma and Immunology, 2014.
[68] M. Malerba, A. Radaeli, A. Olivini, G. Damiani, B. Ragnoli, P. Montuschi, and F. L. M. Ricciardolo, “Exhaled nitric oxide as a biomarker in COPD and related comorbidities.,” BioMed Research International, vol. 2014. 2014.
[69] A. P. Chua, L. S. Aboussouan, O. A. Minai, K. Paschke, D. Laskowski, and R. A. Dweik, “Long-term continuous positive airway pressure therapy normalizes high exhaled nitric oxide levels in obstructive sleep apnea.,” J. Clin. Sleep Med., vol. 9, no. 6, pp. 529–35, Jan. 2013.
[70] P. E. Silkoff, M. Caramori, L. Tremblay, P. McClean, C. Chaparro, S. Kesten, M. Hutcheon, A. S. Slutsky, N. Zamel, and S. Keshavjee, “Exhaled nitric oxide in human lung transplantation. A noninvasive marker of acute rejection.,” Am. J. Respir. Crit. Care Med., vol. 157, no. 6 Pt 1, pp. 1822–8, Jun. 1998.
[71] M. A. Gashouta, C. A. Merlo, M. R. Pipeling, J. F. McDyer, J. W. A. Hayanga, J. B. Orens, and R. E. Girgis, “Serial monitoring of exhaled nitric oxide in lung transplant recipients.,” J. Heart Lung Transplant., vol. 34, no. 4, pp. 557–62, Apr. 2015.
[72] N. Kamada and R. Y. Calne, “Orthotopic liver transplantation in the rat. Technique using cuff for portal vein anastomosis and biliary drainage.,” Transplantation, vol. 28, no. 1, pp. 47–50, Jul. 1979.
[73] R. A. Jordan and J. B. Schenkman, “Relationship between malondialdehyde production and arachidonate consumption during NADPH-supported microsomal lipid peroxidation.,” Biochem. Pharmacol., vol. 31, no. 7, pp. 1393–400, Apr. 1982.
[74] L. Baird and A. T. Dinkova-Kostova, “The cytoprotective role of the Keap1-Nrf2 pathway.,” Arch. Toxicol., vol. 85, no. 4, pp. 241–272, 2011.
[75] M. B. Sporn and K. T. Liby, “NRF2 and cancer: the good, the bad and the importance of context.,” Nat. Rev. Cancer, vol. 12, no. 8, pp. 564–71, Aug. 2012.
[76] D. A. Bloom and A. K. Jaiswal, “Phosphorylation of Nrf2 at Ser40 by protein kinase C in response to antioxidants leads to the release of Nrf2 from INrf2, but is not required for Nrf2 stabilization/accumulation in the nucleus and transcriptional activation of antioxidant response element,” J. Biol. Chem., vol. 278, no. 45, pp. 44675–82, Nov. 2003.
[77] T. Nguyen, P. J. Sherratt, H. C. Huang, C. S. Yang, and C. B. Pickett, “Increased protein stability as a mechanism that enhances Nrf2-mediated transcriptional activation of the antioxidant response element: Degradation of Nrf2 by the 26 S proteasome.,” J. Biol. Chem., vol. 278, no. 7, pp. 4536–4541, 2003.
[78] M. O. Song, C. H. Lee, H. O. Yang, and J. H. Freedman, “Endosulfan upregulates AP-1 binding and ARE-mediated transcription via ERK1/2 and p38 activation in HepG2 cells.,” Toxicology, vol. 292, no. 1, pp. 23–32, Feb. 2012.
[79] R. Kachadourian, S. Pugazhenthi, K. Velmurugan, D. S. Backos, C. C. Franklin, J. M. McCord, and B. J. Day, “2’,5'-Dihydroxychalcone-induced glutathione is mediated by oxidative stress and kinase signaling pathways.,” Free Radic. Biol. Med., vol. 51, no. 6, pp. 1146–1154, 2011.
[80] B. M. Choi, S. M. Kim, T. K. Park, G. Li, S. J. Hong, R. Park, H. T. Chung, and B. R. Kim, “Piperine protects cisplatin-induced apoptosis via heme oxygenase-1 induction in auditory cells.,” J. Nutr. Biochem., vol. 18, no. 9, pp. 615–622, 2007.
[81] Z. Sun, Z. Huang, and D. D. Zhang, “Phosphorylation of Nrf2 at multiple sites by MAP kinases has a limited contribution in modulating the Nrf2-dependent antioxidant response.,” PLoS One, vol. 4, no. 8, 2009.
[82] L. M. Zipper and R. T. Mulcahy, “Erk activation is required for Nrf2 nuclear localization during pyrrolidine dithiocarbamate induction of glutamate cysteine ligase modulatory gene expression in HepG2 cells.,” Toxicol. Sci., vol. 73, no. 1, pp. 124–134, 2003.
[83] E. J. Park, Y. M. Kim, S. W. Park, H. J. Kim, J. H. Lee, D. U. Lee, and K. C. Chang, “Induction of HO-1 through p38 MAPK/Nrf2 signaling pathway by ethanol extract of Inula helenium L. reduces inflammation in LPS-activated RAW 264.7 cells and CLP-induced septic mice.,” Food Chem. Toxicol., vol. 55, pp. 386–395, 2013.
[84] E. Hu, J. B. Kim, P. Sarraf, and B. M. Spiegelman, “Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARgamma.,” Science, vol. 274, no. 5295, pp. 2100–2103, 1996.
[85] Q. F. Collins, Y. Xiong, E. G. Lupo, H. Y. Liu, and W. Cao, “p38 Mitogen-activated protein kinase mediates free fatty acid-induced gluconeogenesis in hepatocytes.,” J. Biol. Chem., vol. 281, no. 34, pp. 24336–24344, 2006.
[86] Y. Tsuchiya, I. Minami, H. Kadotani, T. Todo, and E. Nishida, “Circadian clock-controlled diurnal oscillation of Ras/ERK signaling in mouse liver.,” Proc. Jpn. Acad. Ser. B. Phys. Biol. Sci., vol. 89, no. 1, pp. 59–65, 2013.
[87] J. Lee, C. Sun, Y. Zhou, J. Lee, D. Gokalp, H. Herrema, S. W. Park, R. J. Davis, and U. Ozcan, “p38 MAPK–mediated regulation of Xbp1s is crucial for glucose homeostasis.,” Nat. Med., vol. 17, no. 10, pp. 1251–1260, 2011.
[88] B. P. Sampey, D. L. Carbone, J. A. Doorn, D. A. Drechsel, and D. R. Petersen, “4-Hydroxy-2-nonenal adduction of extracellular signal-regulated kinase (Erk) and the inhibition of hepatocyte Erk-Est-like protein-1-activating protein-1 signal transduction.,” Mol. Pharmacol., vol. 71, no. 3, pp. 871–883, 2007.
[89] M. Crompton, “The mitochondrial permeability transition pore and its role in cell death.,” Biochem. J., vol. 341 ( Pt 2, pp. 233–249, 1999.
[90] S. Elmore, “Apoptosis: a review of programmed cell death.,” Toxicol. Pathol., vol. 35, no. 4, pp. 495–516, 2007.
[91] T. Ohtsubo, S. Kamada, T. Mikami, H. Murakami, and Y. Tsujimoto, “Identification of NRF2, a member of the NF-E2 family of transcription factors, as a substrate for caspase-3(-like) proteases.,” Cell Death Differ., vol. 6, no. 9, pp. 865–872, 1999.
[92] Q. Huang, F. Li, X. Liu, W. Li, W. Shi, F. F. Liu, B. O’Sullivan, Z. He, Y. Peng, A. C. Tan, L. Zhou, J. Shen, G. Han, X. J. Wang, J. Thorburn, A. Thorburn, A. Jimeno, D. Raben, J. S. Bedford, and C. Y. Li, “Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy.,” Nat. Med., vol. 17, no. 7, pp. 860–866, 2011.
[93] K. J. Wood, A. Bushell, and J. Hester, “Regulatory immune cells in transplantation.,” Nat. Rev. Immunol., vol. 12, no. 6, pp. 417–430, 2012.
[94] L. E. Prestes-Carneiro, M. T. Shio, P. D. Fernandes, and S. Jancar, “Cross-regulation of iNOS and COX-2 by its products in murine macrophages under stress conditions.,” Cell. Physiol. Biochem., vol. 20, no. 5, pp. 283–292, 2007.
[95] K. Uno, Y. Iuchi, J. Fujii, H. Sugata, K. Iijima, K. Kato, T. Shimosegawa, and T. Yoshimura, “In vivo study on cross talk between inducible nitric-oxide synthase and cyclooxygenase in rat gastric mucosa: effect of cyclooxygenase activity on nitric oxide production.,” J. Pharmacol. Exp. Ther., vol. 309, no. 3, pp. 995–1002, 2004.
[96] M. Hori, M. Kita, S. Torihashi, S. Miyamoto, K. J. Won, K. Sato, H. Ozaki, and H. Karaki, “Upregulation of iNOS by COX-2 in muscularis resident macrophage of rat intestine stimulated with LPS.,” Am. J. Physiol. Gastrointest. Liver Physiol., vol. 280, no. 5, pp. G930–G938, 2001.
[97] P. O. T. Tran, C. E. Gleason, and R. P. Robertson, “Inhibition of interleukin-1beta-induced COX-2 and EP3 gene expression by sodium salicylate enhances pancreatic islet beta-cell function.,” Diabetes, vol. 51, no. 6, pp. 1772–1778, 2002.
[98] D. A. Geller, M. E. De Vera, D. A. Russell, R. A. Shapiro, K. N. Andreas, R. Simmons, and T. R. Billiar, “A Central Role for IL-lβ in the In Vitro and In Vivo Regulation of Hepatic Inducible Nitric Oxide Synthase.,” J. Immunol., vol. 155, pp. 4890–4898, 1995.
[99] J. Yu, E. Ip, A. Dela Peña, Y. H. Jing, J. Sesha, N. Pera, P. Hall, R. Kirsch, I. Leclercq, and G. C. Farrell, “COX-2 induction in mice with experimental nutritional steatohepatitis: Role as pro-inflammatory mediator.,” Hepatology, vol. 43, no. 4, pp. 826–836, 2006.
[100] J. Muntané, F. J. Rodríguez, O. Segado, A. Quintero, J. M. Lozano, E. Siendones, C. a Pedraza, M. Delgado, F. O’Valle, R. García, J. L. Montero, M. De La Mata, and G. Miño, “TNF-alpha dependent production of inducible nitric oxide is involved in PGE1 protection against acute liver injury.,” Gut, vol. 47, no. 4, pp. 553–562, 2000.
[101] G. Sass, K. Koerber, R. Bang, H. Guehring, and G. Tiegs, “Inducible nitric oxide synthase is critical for immune-mediated liver injury in mice.,” J. Clin. Invest., vol. 107, no. 4, pp. 439–447, 2001.
[102] D. E. Tache, C. E. Stănciulescu, I. M. Baniţă, Ş. O. Purcaru, A. M. Andrei, V. Comănescu, and C. G. Pisoschi, “Inducible nitric oxide synthase expression (iNOS) in chronic viral hepatitis and its correlation with liver fibrosis.,” Rom. J. Morphol. Embryol., vol. 55, no. 2 Suppl, pp. 539–43, Jan. 2014.
[103] G. M. Zou, “Interaction Between Macrophages, TGF-b1, and the COX-2 Pathway During the Inflammatory Phase of Skeletal Muscle Healing After Injury,” J. Cell. Physiol., vol. 213, no. 2, pp. 440–444, 2007.
[104] T. J. Martelius, H. Wolff, C. a. Bruggeman, K. a. Höckerstedt, and I. T. Lautenschlager, “Induction of cyclo-oxygenase-2 by acute liver allograft rejection and cytomegalovirus infection in the rat.,” Transpl. Int., vol. 15, no. 12, pp. 610–614, 2002.
[105] P. C. Kuo, E. J. Alfrey, N. R. Krieger, K. Y. Abe, P. Huie, R. K. Sibley, and D. C. Dafoe, “Differential localization of allograft nitric oxide synthesis: comparison of liver and heart transplantation in the rat model.,” Immunology, vol. 87, no. 4, pp. 647–653, 1996.