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Jahagirdar V, Ahmed M, Fatima I, Ali H, Alba L, Helzberg JH, Cummings LS, Wilkinson M, Forster J, Likhitsup A. Prostaglandin E1 administration post liver transplantation and renal outcomes: A retrospective single center experience. World J Transplant 2024; 14:98797. [PMID: 39697460 PMCID: PMC11438947 DOI: 10.5500/wjt.v14.i4.98797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 08/21/2024] [Accepted: 09/02/2024] [Indexed: 09/20/2024] Open
Abstract
BACKGROUND Prostaglandin E1 (PGE1), or alprostadil, is a potent vasodilator that improves hepatic blood flow and reduces ischemia-reperfusion injury post-liver transplantation (LT). However, the benefits of PGE1 on renal function after LT have not yet been well described. AIM To assess the impact of PGE1 administration on renal function in patients who underwent liver or liver-kidney transplant. METHODS This retrospective study included all patients who underwent liver or liver-kidney transplant at our institution from January, 2011 to December, 2021. Patients were classified based on whether they received PGE1. PGE1 was administered post-LT to those with transaminases > 1000 U/L in the immediate postoperative period. Demographics, post-LT treatments and/or complications, renal function, and survival were analyzed. Multivariable logistic regression analysis was performed, and a two-tailed P value < 0.05 was considered statistically significant. RESULTS A total of 145 patients underwent LT, with 44 (30%) receiving PGE1. Baseline patient characteristics were comparable, except the PGE1 group had significantly higher aspartate aminotransferase (AST) (1961.9 U/L ± 1862.3 U/L vs 878 U/L ± 741.4 U/L, P = 0.000), alanine aminotransferase (1070.6 U/L ± 895 U/L vs 547.7 U/L ± 410 U/L, P = 0.000), international normalized ratio on post-LT day 1 (2 ± 0.74 vs 1.8 ± 0.4, P = 0.03), a longer intensive care unit stay (8.1 days ± 11.8 days vs 3.8 days ± 4.6 days, P = 0.003), more vasopressor use (55.53 hours ± 111 hours vs 16.33 hours ± 26.3 hours, P = 0.002), and higher immediate postoperative complications (18.6% vs 4.9%, P = 0.04). The PGE1 group also had a significantly higher 90-day readmission rate (29.6% vs 13.1%, P = 0.02) and lower 1-year liver graft survival (87.5% vs 98.9%, P = 0.005). However, 30-day readmission (31.6% vs 27.4%, P = 0.64), LT complications (hepatic artery thrombosis, biliary complications, rejection of liver graft, cardiomyopathy), 1-year patient survival (96.9% vs 97.8%, P = 0.77), overall liver graft survival, and overall patient survival were similar between the two groups (95.4% vs 93.9%, P = 0.74 and 88.4% vs 86.9%, P = 0.81 respectively). Although the PGE1 group had a significantly lower glomerular filtration rate (eGFR) on post-LT day 7 (46.3 mL/minute ± 26.7 mL/minute vs 62.5 mL/minute ± 34 mL/minute, P = 0.009), the eventual need for renal replacement therapy (13.6% vs 5.9%, P = 0.09), the number of dialysis sessions (0.91 vs 0.27, P = 0.13), and eGFR at 1-month (37.2 mL/minute ± 35.9 mL/minute vs 42 mL/minute ± 36.9 mL/minute, P = 0.49), 6-months (54.8 mL/minute ± 21.6 mL/minute vs 62 mL/minute ± 21.4 mL/minute, P = 0.09), and 12-months (63.7 mL/minute ± 20.7 mL/minute vs 62.8 mL/minute ± 20.3 mL/minute, P = 0.85) post-LT were similar to those in the non-PGE1 group. CONCLUSION In patients who received PGE1 for ischemia-reperfusion injury, despite immediate acute renal injury post-LT, the renal function at 1-month, 6-months, and 12-months post-LT was similar compared to those without ischemia-reperfusion injury. Prospective clinical trials are needed to further elucidate the benefits of PGE1 use in renal function.
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Affiliation(s)
- Vinay Jahagirdar
- Department of Internal Medicine, Saint Luke’s Health System of Kansas City and the University of Missouri-Kansas City, Kansas City, MO 64111, United States
| | - Mohamed Ahmed
- Department of Internal Medicine, Saint Luke’s Health System of Kansas City and the University of Missouri-Kansas City, Kansas City, MO 64111, United States
| | - Ifrah Fatima
- Department of Internal Medicine, Saint Luke’s Health System of Kansas City and the University of Missouri-Kansas City, Kansas City, MO 64111, United States
| | - Hassam Ali
- Department of Gastroenterology and Hepatology, East Carolina University Brody School of Medicine, Greenville, NC 27834, United States
| | - Laura Alba
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, Saint Luke’s Health System of Kansas City and University of Missouri-Kansas City, Kansas City, MO 64111, United States
| | - John H Helzberg
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, Saint Luke’s Health System of Kansas City and University of Missouri-Kansas City, Kansas City, MO 64111, United States
| | - Lee S Cummings
- Department of Surgery, University of Missouri-Kansas City and Transplant Surgery, Saint Luke’s Hospital of Kansas City, Kansas City, MO 64111, United States
| | - Matthew Wilkinson
- Department of Surgery, University of Missouri-Kansas City and Transplant Surgery, Saint Luke’s Hospital of Kansas City, Kansas City, MO 64111, United States
| | - Jameson Forster
- Department of Surgery, University of Missouri-Kansas City and Transplant Surgery, Saint Luke’s Hospital of Kansas City, Kansas City, MO 64111, United States
| | - Alisa Likhitsup
- Department of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI 48109, United States
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Garcia KB, Hussein A, Satish S, Wehrle CJ, Karakaya O, Panconesi R, Sun K, Jiao C, Fernandes E, Pinna A, Hashimoto K, Miller C, Aucejo F, Schlegel A. Machine Perfusion as a Strategy to Decrease Ischemia-Reperfusion Injury and Lower Cancer Recurrence Following Liver Transplantation. Cancers (Basel) 2024; 16:3959. [PMID: 39682147 DOI: 10.3390/cancers16233959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 11/12/2024] [Accepted: 11/13/2024] [Indexed: 12/18/2024] Open
Abstract
Liver transplantation (LT) is a key treatment for primary and secondary liver cancers, reducing tumor burden with concurrent improvement of liver function. While significant improvement in survival is noted with LT, cancer recurrence rates remain high. Mitochondrial dysfunction caused by ischemia-reperfusion injury (IRI) is known to drive tumor recurrence by creating a favorable microenvironment rich in pro-inflammatory and angiogenic factors. Therefore, strategies that decrease reperfusion injury and mitochondrial dysfunction may also decrease cancer recurrence following LT. Machine perfusion techniques are increasingly used in routine clinical practice of LT with improved post-transplant outcomes and increased use of marginal grafts. Normothermic (NMP) and hypothermic oxygenated machine perfusion (HOPE) provide oxygen to ischemic tissues, and impact IRI and potential cancer recurrence through different mechanisms. This article discussed the link between IRI-associated inflammation and tumor recurrence after LT. The current literature was screened for the role of machine perfusion as a strategy to mitigate the risk of cancer recurrence. Upfront NMP ("ischemia free organ transplantation") and end-ischemic HOPE were shown to reduce hepatocellular carcinoma recurrence in retrospective studies. Three prospective randomized controlled trials are ongoing in Europe to provide robust evidence on the impact of HOPE on cancer recurrence in LT.
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Affiliation(s)
- Karla Bracho Garcia
- Department of Liver Transplantation, Cleveland Clinic Weston Hospital, Weston, FL 33331, USA
| | - Ahmed Hussein
- Department of Liver Transplantation, Cleveland Clinic Weston Hospital, Weston, FL 33331, USA
| | - Sangeeta Satish
- Transplantation Center, Department of Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Chase J Wehrle
- Transplantation Center, Department of Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Omer Karakaya
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Rebecca Panconesi
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Keyue Sun
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Chunbao Jiao
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Eduardo Fernandes
- Department of Liver Transplantation, Cleveland Clinic Weston Hospital, Weston, FL 33331, USA
| | - Antonio Pinna
- Department of Liver Transplantation, Cleveland Clinic Weston Hospital, Weston, FL 33331, USA
| | - Koji Hashimoto
- Transplantation Center, Department of Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Charles Miller
- Transplantation Center, Department of Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Federico Aucejo
- Transplantation Center, Department of Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Andrea Schlegel
- Transplantation Center, Department of Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
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Mohamed ZU, Varghese CT, Sudhakar A, Kumar L, Gopalakrishnan U, Balakrishnan D, Narayanamenon R, Sudhindran S. Prostaglandins for adult liver transplanted recipients. Cochrane Database Syst Rev 2023; 8:CD006006. [PMID: 37540003 PMCID: PMC10401650 DOI: 10.1002/14651858.cd006006.pub3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/05/2023]
Abstract
BACKGROUND Prostaglandins are naturally occurring lipids that are synthesised from arachidonic acid. Multiple studies have evaluated the benefits of prostaglandins in reducing ischaemia reperfusion injury after liver transplantation. New studies have been published since the previous review, and hence it was important to update the evidence for this intervention. OBJECTIVES To evaluate the benefits and harms of prostaglandins in adults undergoing liver transplantation compared with placebo or standard care. SEARCH METHODS We used standard, extensive Cochrane search methods. The latest search date was 27 December 2022. SELECTION CRITERIA We included randomised clinical trials evaluating prostaglandins initiated in the perioperative period compared with placebo or standard care for adults undergoing liver transplantation. We included trials irrespective of reported outcomes. DATA COLLECTION AND ANALYSIS We used standard Cochrane methods. Our primary outcomes were 1. all-cause mortality, 2. serious adverse events, and 3. health-related quality of life. Our secondary outcomes were 4. liver retransplantation, 5. early allograft dysfunction, 6. primary non-function of the allograft, 7. acute kidney failure, 8. length of hospital stay, and 9. adverse events considered non-serious. We used GRADE to assess certainty of evidence. MAIN RESULTS We included 11 randomised clinical trials with 771 adult liver transplant recipients (mean age 47.31 years, male 61.48%), of whom 378 people were randomised to receive prostaglandins and 393 people were randomised to either placebo (272 participants) or standard care (121 participants). All trials were published between 1993 and 2016. Ten trials were conducted in high- and upper-middle-income countries. Prostaglandins may reduce all-cause mortality up to one month (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.61 to 1.23; risk difference (RD) 21 fewer per 1000, 95% CI 63 fewer to 36 more; 11 trials, 771 participants; low-certainty evidence). Prostaglandins may result in little to no difference in serious adverse events (RR 0.92, 95% CI 0.60 to 1.40; RD 81 fewer per 1000, 95% CI 148 fewer to 18 more; 6 trials, 568 participants; low-certainty evidence). None of the included trials reported health-related quality of life. Prostaglandins may result in little to no difference in liver retransplantation (RR 0.98, 95% CI 0.49 to 1.96; RD 1 fewer per 1000, 95% CI 33 fewer to 62 more; 6 trials, 468 participants; low-certainty evidence); early allograft dysfunction (RR 0.62, 95% CI 0.33 to 1.18; RD 137 fewer per 1000, 95% CI 241 fewer to 47 more; 1 trial, 99 participants; low-certainty evidence); primary non-function of the allograft (RR 0.58, 95% CI 0.26 to 1.32; RD 23 fewer per 1000, 95% CI 40 fewer to 16 more; 7 trials, 624 participants; low-certainty evidence); and length of hospital stay (mean difference (MD) -1.15 days, 95% CI -5.44 to 3.14; 4 trials, 369 participants; low-certainty evidence). Prostaglandins may result in a large reduction in the development of acute kidney failure requiring dialysis (RR 0.42, 95% CI 0.24 to 0.73; RD 100 fewer per 1000, 95% CI 132 fewer to 49 fewer; 5 trials, 477 participants; low-certainty evidence). The evidence is very uncertain about the effect of prostaglandins on adverse events considered non-serious (RR 1.19, 95% CI 0.42 to 3.36; RD 225 fewer per 1000, 95% CI 294 fewer to 65 fewer; 4 trials, 329 participants; very low-certainty evidence). Two trials reported receiving funding; one of these was with vested interests. We found one registered ongoing trial. AUTHORS' CONCLUSIONS Eleven trials evaluated prostaglandins in adult liver transplanted recipients. Based on low-certainty evidence, prostaglandins may reduce all-cause mortality up to one month; may cause little to no difference in serious adverse events, liver retransplantation, early allograft dysfunction, primary non-function of the allograft, and length of hospital stay; and may have a large reduction in the development of acute kidney injury requiring dialysis. We do not know the effect of prostaglandins on adverse events considered non-serious. We lack adequately powered, high-quality trials evaluating the effects of prostaglandins for people undergoing liver transplantation.
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Affiliation(s)
- Zubair Umer Mohamed
- Department of Anaesthesia and Intensive Care, Amrita Institute of Medical Sciences, Kochi, India
- Department of Critical Care, King Faisal Specialist Hospital and Research Centre, Madinah, Saudi Arabia
| | - Christi Titus Varghese
- Department of Gastrointestinal Surgery and Solid Organ Transplantation, Amrita Institute of Medical Sciences, Kochi, India
| | - Abish Sudhakar
- Department of Paediatric Cardiology, Amrita Institute of Medical Sciences, Kochi, India
| | - Lakshmi Kumar
- Department of Anaesthesia and Intensive Care, Amrita Institute of Medical Sciences, Kochi, India
| | - Unnikrishnan Gopalakrishnan
- Department of Gastrointestinal Surgery and Solid Organ Transplantation, Amrita Institute of Medical Sciences, Kochi, India
| | - Dinesh Balakrishnan
- Department of Gastrointestinal Surgery and Solid Organ Transplantation, Amrita Institute of Medical Sciences, Kochi, India
| | - Ramachandran Narayanamenon
- Department of Gastrointestinal Surgery and Solid Organ Transplantation, Amrita Institute of Medical Sciences, Kochi, India
| | - Surendran Sudhindran
- Department of Gastrointestinal Surgery and Solid Organ Transplantation, Amrita Institute of Medical Sciences, Kochi, India
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Azırak S. Prevention of nephrotoxicity induced by amikacin: The role of misoprostol, A prostaglandin E1 analogue. Prostaglandins Other Lipid Mediat 2023; 164:106682. [PMID: 36349661 DOI: 10.1016/j.prostaglandins.2022.106682] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 10/26/2022] [Accepted: 10/27/2022] [Indexed: 11/05/2022]
Abstract
Amikacin (AK) is an aminoglycoside that is widely used to treat life-threatening Gram-negative infections, especially in intensive care units. Despite its wide clinical indications, AK causes serious side effects such as kidney toxicity. AK was found to lead to tissue damage primarily through apoptosis and oxidative stress. Therefore, it was investigated whether misoprostol (MP), which has antioxidant and antiapoptotic properties, had a beneficial effect on kidney damage caused by AK. It was observed that kidney injury molecule-1 (KIM-1) mRNA, blood urea nitrogen (BUN), creatinine (Cr), NADPH oxidase-4 (NOX-4) and Caspase-3 (CAS-3) levels increased in the AK-treated group in comparison with the control group, while uric acid, albumin, and total protein levels were decreased. In rats that were treated with AK+MP, the levels of KIM-1 mRNA, BUN, Cr, NOX-4 and CAS-3 were significantly decreased in comparison with the AK group, while uric acid, albumin and total protein levels increased. According to the obtained results, MP was found to be quite effective in the protection of kidneys from the toxic effects of AK.
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Affiliation(s)
- Sebile Azırak
- Vocational School of Health Services, University of Adıyaman, Adıyaman, Turkey.
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Shen Y, Wang X, Yuan R, Pan X, Yang X, Cai J, Li Y, Yin A, Xiao Q, Ji Q, Li Y, He B, Shen L. Prostaglandin E1 attenuates AngII-induced cardiac hypertrophy via EP3 receptor activation and Netrin-1upregulation. J Mol Cell Cardiol 2021; 159:91-104. [PMID: 34147480 DOI: 10.1016/j.yjmcc.2021.06.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 05/27/2021] [Accepted: 06/13/2021] [Indexed: 01/09/2023]
Abstract
AIMS Pathological cardiac hypertrophy induced by activation of the renin-angiotensin-aldosterone system (RAAS) is one of the leading causes of heart failure. However, in current clinical practice, the strategy for targeting the RAAS is not sufficient to reverse hypertrophy. Here, we investigated the effect of prostaglandin E1 (PGE1) on angiotensin II (AngII)-induced cardiac hypertrophy and potential molecular mechanisms underlying the effect. METHODS AND RESULTS Adult male C57 mice were continuously infused with AngII or saline and treated daily with PGE1 or vehicle for two weeks. Neonatal rat cardiomyocytes were cultured to detect AngII-induced hypertrophic responses. We found that PGE1 ameliorated AngII-induced cardiac hypertrophy both in vivo and in vitro. The RNA sequencing (RNA-seq) and expression pattern analysis results suggest that Netrin-1 (Ntn1) is the specific target gene of PGE1. The protective effect of PGE1 was eliminated after knockdown of Ntn1. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the PGE1-mediated signaling pathway changes are associated with the mitogen-activated protein kinase (MAPK) pathway. PGE1 suppressed AngII-induced activation of the MAPK signaling pathway, and such an effect was attenuated by Ntn1 knockdown. Blockade of MAPK signaling rescued the phenotype of cardiomyocytes caused by Ntn1 knockdown, indicating that MAPK signaling may act as the downstream effector of Ntn1. Furthermore, inhibition of the E-prostanoid (EP) 3 receptor, as opposed to the EP1, EP2, or EP4 receptor, in cardiomyocytes reversed the effect of PGE1, and activation of EP3 by sulprostone, a specific agonist, mimicked the effect of PGE1. CONCLUSION In conclusion, PGE1 ameliorates AngII-induced cardiac hypertrophy through activation of the EP3 receptor and upregulation of Ntn1, which inhibits the downstream MAPK signaling pathway. Thus, targeting EP3, as well as the Ntn1-MAPK axis, may represent a novel approach for treating pathological cardiac hypertrophy.
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Affiliation(s)
- Yejiao Shen
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xia Wang
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Ruosen Yuan
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xin Pan
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoxiao Yang
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Jiali Cai
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yi Li
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Anwen Yin
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Qingqing Xiao
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Qingqi Ji
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yanjie Li
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Ben He
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
| | - Linghong Shen
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
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Arisaka S, Matsuyama R, Goto K, Suwa Y, Mori R, Morioka D, Taguri M, Endo I. Predictive Ability of Preoperative PT-INR and Postoperative MCP1 for Post-hepatectomy Liver Failure. In Vivo 2021; 34:1255-1263. [PMID: 32354916 DOI: 10.21873/invivo.11899] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 03/09/2020] [Accepted: 03/12/2020] [Indexed: 01/13/2023]
Abstract
BACKGROUND We sought a diagnostic tool using perioperative variables that might predict post-hepatectomy liver failure (PHLF). PATIENTS AND METHODS In 68 patients undergoing major hepatectomy, data on inflammatory markers and coagulation factors were prospectively collected and were compared between patients with International Study Group of Liver Surgery definition grade B/C PHLF (LF group) and those without LF (non-LF group). RESULTS Preoperatively, the LF group (n=9; 13.2%) had a lower platelet count and a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13) activity and a higher prothrombin time-International Normalized Ratio (PT-INR) than the non-LF group. On postoperative day 1, the LF group had significantly higher serum interleukin 6 (IL6), C-C motif chemokine ligand 2 (CCL2), and IL10 levels than the non-LF group. The logistic regression model that included preoperative PT-INR and CCL2 on postoperative day 1 predicted grade B/C PHLF with 100% sensitivity and 89.8% specificity. CONCLUSION Our findings suggest that the combination of preoperative PT-INR and CCL2 on postoperative day 1 can predict PHLF earlier and precisely after major hepatectomy.
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Affiliation(s)
- Sayaka Arisaka
- Department of Gastroenterological Surgery, Yokohama City University, Yokohama, Japan
| | - Ryusei Matsuyama
- Department of Gastroenterological Surgery, Yokohama City University, Yokohama, Japan
| | - Koki Goto
- Department of Gastroenterological Surgery, Yokohama City University, Yokohama, Japan
| | - Yusuke Suwa
- Department of Gastroenterological Surgery, Yokohama City University, Yokohama, Japan
| | - Ryutaro Mori
- Department of Gastroenterological Surgery, Yokohama City University, Yokohama, Japan
| | - Daisuke Morioka
- Department of Gastroenterological Surgery, Yokohama City University, Yokohama, Japan
| | - Masataka Taguri
- Department of Biostatistics, Yokohama City University, Yokohama, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University, Yokohama, Japan
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Du Y, Taylor CG, Aukema HM, Zahradka P. Role of oxylipins generated from dietary PUFAs in the modulation of endothelial cell function. Prostaglandins Leukot Essent Fatty Acids 2020; 160:102160. [PMID: 32717531 DOI: 10.1016/j.plefa.2020.102160] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 07/17/2020] [Accepted: 07/17/2020] [Indexed: 12/13/2022]
Abstract
Oxylipins, which are circulating bioactive lipids generated from polyunsaturated fatty acids (PUFAs) by cyclooxygenase, lipooxygenase and cytochrome P450 enzymes, have diverse effects on endothelial cells. Although studies of the effects of oxylipins on endothelial cell function are accumulating, a review that provides a comprehensive compilation of current knowledge and recent advances in the context of vascular homeostasis is lacking. This is the first compilation of the various in vitro, ex vivo and in vivo reports to examine the effects and potential mechanisms of action of oxylipins on endothelial cells. The aggregate data indicate docosahexaenoic acid-derived oxylipins consistently show beneficial effects related to key endothelial cell functions, whereas oxylipins derived from other PUFAs exhibit both positive and negative effects. Furthermore, information is lacking for certain oxylipin classes, such as those derived from α-linolenic acid, which suggests additional studies are required to achieve a full understanding of how oxylipins affect endothelial cells.
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Affiliation(s)
- Youjia Du
- Canadian Centre for Agri-Food Research in Health and Medicine, St Boniface Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada; Department of Physiology and Pathophysiology, University of Manitoba, MB R3E 0J9, Canada
| | - Carla G Taylor
- Canadian Centre for Agri-Food Research in Health and Medicine, St Boniface Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada; Department of Physiology and Pathophysiology, University of Manitoba, MB R3E 0J9, Canada; Department of Food and Human Nutritional Sciences, University of Manitoba, MB R3T 2N2, Canada
| | - Harold M Aukema
- Canadian Centre for Agri-Food Research in Health and Medicine, St Boniface Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada; Department of Food and Human Nutritional Sciences, University of Manitoba, MB R3T 2N2, Canada
| | - Peter Zahradka
- Canadian Centre for Agri-Food Research in Health and Medicine, St Boniface Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada; Department of Physiology and Pathophysiology, University of Manitoba, MB R3E 0J9, Canada; Department of Food and Human Nutritional Sciences, University of Manitoba, MB R3T 2N2, Canada.
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Li J, Jiang J, Chu Z, Zhang Y, Cai W, Zhu J, Grimm R, Ji Q. Multiparametric MRI Evaluation of Liposomal Prostaglandins E1 Intervention on Hepatic Warm Ischemia‐Reperfusion Injury in Rabbits. J Magn Reson Imaging 2019; 52:217-228. [PMID: 31829483 DOI: 10.1002/jmri.27022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Revised: 11/25/2019] [Accepted: 11/26/2019] [Indexed: 01/19/2023] Open
Affiliation(s)
- Jingyao Li
- First Central Clinical College of Tianjin Medical University Nankai DistrictTianjin China
- Department of RadiologyTianjin First Central Hospital Nankai DistrictTianjin China
| | - Jiabing Jiang
- First Central Clinical College of Tianjin Medical University Nankai DistrictTianjin China
- Department of RadiologyTianjin First Central Hospital Nankai DistrictTianjin China
| | - Zhiqiang Chu
- Department of TransplantationTianjin First Central Hospital Nankai DistrictTianjin China
| | - Yuling Zhang
- First Central Clinical College of Tianjin Medical University Nankai DistrictTianjin China
- Department of RadiologyTianjin First Central Hospital Nankai DistrictTianjin China
| | - Wenjuan Cai
- Department of PathologyTianjin First Central Hospital Nankai DistrictTianjin China
| | - Jinxia Zhu
- MR Collaboration, Siemens Healthcare Beijing China
| | | | - Qian Ji
- Department of RadiologyTianjin First Central Hospital Nankai DistrictTianjin China
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Cho M, Kim WS, Shin H, Yun IJ. Effect of Prostaglandin E 1 Injected Into Donors in a Heterotopic Heart Transplant Model of Sprague Dawley Rats. Transplant Proc 2019; 51:2808-2813. [PMID: 31563248 DOI: 10.1016/j.transproceed.2019.01.198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 01/28/2019] [Indexed: 11/16/2022]
Abstract
INTRODUCTION Prostaglandin E1 (PGE1) administered to patients in the immediate post-transplant period has been known to reduce ischemic reperfusion injuries (IRIs), but the effect on IRI of PGE1 administered to the donor is unknown. The purpose of this study was to determine the effect on IRI of PGE1 injected into donor rats during heterotopic heart transplantation. METHODS Genetically identical male Sprague Dawley rats with a body weight of 300-320 g at 8-9 weeks of age were used for the study. Experimental methods were the same in the control (G0, n = 6) and experimental groups (G1, n = 6), but only the donor rats in the experimental group received an intramuscular injection of PGE1 (5 μg/kg) prior to the donor surgery. On day 1 the animals were sacrificed with the removal of the transplanted heart. Histologic analysis was performed in the hematoxylin-eosin-stained slides to assess interstitial edema and neutrophil infiltration by a pathologist. RESULTS Median times of the donor organ procurement, cold ischemia, and warm ischemia were 37, 69, and 35 minutes, respectively, in the G0 group and 38, 76.5, and 33 minutes respectively in G1 group; there were no statistical differences. Heartbeats were observed in the transplanted graft in 2 of the G0 group and 2 of G1 group immediately after heart transplantation, but in all transplanted grafts on day 1 after surgery. Histologic scores for neutrophil infiltration showed significantly lower in the G1 group than in the G0 group. CONCLUSION PGE1 administration to donors in a rat heart transplantation model may significantly reduce IRI.
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Affiliation(s)
- Minji Cho
- Division of Vascular Surgery, Department of Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Wan-Seop Kim
- Department of Pathology, Konkuk University Hospital, Seoul, Republic of Korea
| | - Hyesun Shin
- Department of Surgery, Konkuk University Hospital, Seoul, Republic of Korea
| | - Ik-Jin Yun
- Department of Surgery, Konkuk University Hospital, Seoul, Republic of Korea.
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Martin EM, Schirmer JM, Jones SL, Davis JL. Pharmacokinetics and ex vivo anti-inflammatory effects of oral misoprostol in horses. Equine Vet J 2019; 51:415-421. [PMID: 30256450 PMCID: PMC6587934 DOI: 10.1111/evj.13024] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 08/14/2018] [Accepted: 09/18/2018] [Indexed: 01/09/2023]
Abstract
BACKGROUND Misoprostol is an E prostanoid (EP) 2, 3 and 4 receptor agonist that is anecdotally used to treat and prevent NSAID-induced GI injury in horses. Misoprostol elicits anti-inflammatory effects in vivo in men and rodents, and inhibits TNFα production in equine leucocytes in vitro. OBJECTIVE Define the pharmacokinetic parameters of oral misoprostol in horses, and determine the inhibitory effect of oral misoprostol administration on equine leucocyte TNFα production in an ex vivo inflammation model. STUDY DESIGN Pharmacokinetic study, ex vivo experimental study. METHODS Six healthy adult horses of mixed breeds were used. In phase one, horses were given 5 μg/kg misoprostol orally, and blood was collected at predetermined times for determination of misoprostol free acid (MFA) by UHPLC-MS/MS. Pharmacokinetic parameters were calculated. In phase two, horses were dosed as in phase one, and blood was collected at T0, 0.5, 1 and 4 h following misoprostol administration for leucocyte isolation. Leucocytes were stimulated with 100 ng/mL LPS, and TNFα mRNA concentrations were determined via quantitative real-time PCR. RESULTS About 5 μg/kg oral misoprostol produced a rapid time to maximum concentration (Tmax ) of 23.4 ± 2.4 min, with a maximum concentration (Cmax ) of 0.29 ± 0.07 ng/mL and area under the curve (AUC0-∞ ) of 0.4 ± 0.12 h ng/mL. LPS stimulation of equine leucocytes ex vivo significantly increased TNFα mRNA concentrations, and there was no significant effect of misoprostol even at the Tmax . MAIN LIMITATIONS Only a single dose was used, and sample size was small. CONCLUSIONS Misoprostol is rapidly absorbed following oral administration in horses, and a single 5 μg/kg dose had no significant inhibitory effect on ex vivo LPS-stimulated TNFα mRNA production in leucocytes. Further studies analysing different dosing strategies, including repeat administration or combination with other anti-inflammatory drugs, are warranted.
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Affiliation(s)
- E. M. Martin
- North Carolina State University College of Veterinary MedicineRaleighNorth CarolinaUSA
| | - J. M. Schirmer
- North Carolina State University College of Veterinary MedicineRaleighNorth CarolinaUSA
| | - S. L. Jones
- North Carolina State University College of Veterinary MedicineRaleighNorth CarolinaUSA
| | - J. L. Davis
- VA‐MD College of Veterinary MedicineBlacksburgVirginiaUSA
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Radojkovic M, Stojanovic M, Stanojevic G, Radojkovic D, Gligorijevic J, Ilic I, Stojanovic N. Ischemic preconditioning vs adenosine vs prostaglandin E1 for protection against liver ischemia/reperfusion injury. ACTA ACUST UNITED AC 2017; 50:e6185. [PMID: 28746468 PMCID: PMC5520221 DOI: 10.1590/1414-431x20176185] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2016] [Accepted: 05/23/2017] [Indexed: 11/21/2022]
Abstract
Ischemia/reperfusion injury is still a major cause of morbidity and mortality during liver surgery and transplantation. A variety of surgical and pharmacological therapeutic strategies have been investigated to minimize the effects of ischemia/reperfusion. The aim of our study was to analyze and compare preventive influences of ischemic preconditioning, adenosine and prostaglandin E1 in the experimental model of hepatic ischemia/reperfusion injury. Adult chinchilla rabbits were divided into four groups: 10 rabbits subjected to liver ischemic preconditioning (3-min period of inflow occlusion followed by a 5-min period of reperfusion) followed by 45 min of Pringle maneuver; 10 rabbits subjected to pre-treatment with intraportal injection of adenosine followed by 45 min of Pringle maneuver; 10 rabbits subjected to pre-treatment with intraportal injection of prostaglandin E1 followed by 45 min of Pringle maneuver; and control group of 10 rabbits subjected to 45 min of inflow liver ischemia without any preconditioning. On the second postoperative day, blood samples were obtained and biochemical parameters of liver function were measured and compared. Liver tissue samples were also obtained and histopathological changes were compared. Based on biochemical and histopathological parameters, it was demonstrated that ischemic preconditioning provided the best protection against hepatic ischemia/reperfusion injury. This was probably due to a wider range of mechanisms of action of this method oriented to reduce oxidative stress and inflammation, and restore liver microcirculation and hepatocyte energy compared to the examined pharmacological strategies.
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Affiliation(s)
- M Radojkovic
- Surgery Department, School of Medicine, University of Nis, Nis, Serbia
| | - M Stojanovic
- Surgery Department, School of Medicine, University of Nis, Nis, Serbia
| | - G Stanojevic
- Surgery Department, School of Medicine, University of Nis, Nis, Serbia
| | - D Radojkovic
- Internal Medicine Department, School of Medicine, University of Nis, Nis, Serbia
| | - J Gligorijevic
- Pathology Department, School of Medicine, University of Nis, Nis, Serbia
| | - I Ilic
- Pathology Department, School of Medicine, University of Nis, Nis, Serbia
| | - N Stojanovic
- School of Medicine, University of Nis, Nis, Serbia
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Attenuation of Portal Hypertension by Continuous Portal Infusion of PGE1 and Immunologic Impact in Adult-to-Adult Living-Donor Liver Transplantation. Transplantation 2013; 95:1521-7. [DOI: 10.1097/tp.0b013e31829150a4] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Hara Y, Akamatsu Y, Maida K, Kashiwadate T, Kobayashi Y, Ohuchi N, Satomi S. A new liver graft preparation method for uncontrolled non-heart-beating donors, combining short oxygenated warm perfusion and prostaglandin E1. J Surg Res 2013; 184:1134-42. [PMID: 23688794 DOI: 10.1016/j.jss.2013.04.030] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2013] [Revised: 03/17/2013] [Accepted: 04/17/2013] [Indexed: 01/03/2023]
Abstract
BACKGROUND To resolve the shortage of donors associated with liver transplantation, the potential uncontrolled non-heart-beating donor (UNHBD) pool is expected to increase. However, warm ischemia-reperfusion injury leads to inferior survival in transplantation using the grafts from UNHBD compared with those from heart-beating donors. To overcome this problem, we developed a new method for preparation of liver grafts from UNHBDs consisting of a combination of short oxygenated warm perfusion (SOWP) and prostaglandin E1 (PGE1). METHODS Using an ex vivo perfusion rat model, we examined the effectiveness of this new method. RESULTS Using SOWP and PGE1 treatment, the total amount of bile production during reperfusion in UNHBD grafts was increased to the same level as that in the heart-beating donor grafts. The addition of PGE1 to SOWP buffer decreased aspartate aminotransferase/alanine aminotransferase and tumor necrosis factor α levels during 1 h of reperfusion. Necrosis and apoptosis were significantly decreased by SOWP + PGE1 treatment. SOWP + PGE1 ameliorated induction of mitochondrial permeability transition, and the total amount of mitochondrial cytochrome c in the SOWP + PGE1 group after reperfusion was kept significantly higher than that in the no treatment group. Cytosolic c-Jun N-terminal protein kinase activation was significantly suppressed by SOWP + PGE1. Decrease in mitochondrial Bcl-2 was suppressed by SOWP alone and SOWP + PGE1 treatment, and Bax in the mitochondria was significantly suppressed by SOWP + PGE1. CONCLUSION SOWP and PGE1 prior to cold preservation significantly improved the function of liver grafts that underwent warm ischemia-reperfusion injury. Therefore, this method might be useful in liver transplantation using UNHBD grafts.
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Affiliation(s)
- Yasuyuki Hara
- Division of Advanced Surgical Science and Technology, Graduate School of Medicine, Tohoku University, Sendai, Japan.
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Bärthel E, Rauchfuss F, Hoyer H, Breternitz M, Jandt K, Settmacher U. The PRAISE study: a prospective, multi-center, randomized, double blinded, placebo-controlled study for the evaluation of iloprost in the early postoperative period after liver transplantation (ISRCTN12622749). BMC Surg 2013; 13:1. [PMID: 23356494 PMCID: PMC3564693 DOI: 10.1186/1471-2482-13-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2012] [Accepted: 01/23/2013] [Indexed: 01/30/2023] Open
Abstract
Background Liver graft dysfunction can deteriorate to complete organ failure and increases perioperative morbidity and mortality after liver transplantation. Therapeutic strategies reducing the rate of graft dysfunction are of current clinical relevance. One approach is the systemic application of prostaglandins, which were demonstrated to be beneficial in reducing ischemia-reperfusion injury. Preliminary data indicate a positive effect of prostacyclin analogue iloprost on allograft viability after liver transplantation. The objective of the study is to evaluate the impact of iloprost in a multi-center trial. Methods/Design A prospective, double-blinded, randomized, placebo-controlled multicenter study in a total of 365 liver transplant recipients was designed to assess the effect of intravenous iloprost after liver transplantation. Primary endpoint will be the primary graft dysfunction characterized as presentation of one or more of the following criteria: ALAT or ASAT level > 2000 IU/ml within the first 7 postoperative days, bilirubine ≥ 10 mg/dl on postoperative day 7; INR ≥ 1.6 on postoperative day 7 or initial non-function. Secondary endpoints are parameters of post-transplant morbidity, like rates of infections, biliary complications, need of clotting factors or renal replacement therapy and the graft and patient survival. Discussion A well-established treatment concept to avoid graft dysfunction after liver transplantation does not exist at the moment. If the data of this research project confirm prior findings, iloprost would improve the general outcome after liver transplantation. Trial Registration German Clinical Trials Register: DRKS00003514. Current Controlled Trials Register: ISRCTN12622749.
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Affiliation(s)
- Erik Bärthel
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Erlanger Allee 101, D-07740, Jena, Germany.
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15
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Shin M, Song SH, Kim JM, Kim SJ, Joh JW, Lee SK, Kwon CHD. Effectiveness of intraportal prostaglandin E1 administration after liver transplantation. Transplant Proc 2012; 44:500-4. [PMID: 22410055 DOI: 10.1016/j.transproceed.2012.01.070] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
PURPOSE Prostaglandin E1 (PGE1) has been used to improve hepatic blood flow and to reduce ischemia reperfusion injuries of allografts in liver transplantation. However, PGE1 undergoes extensive metabolic clearance in the pulmonary and splanchnic circulation during intravenous administration. We analyzed the effect of intraportally administered PGE1. METHODS Sixty living-donor liver transplant recipients received continuous infusions of PGE1 for 10 days immediately after the reperfusion of the allografts. Of them, 40 recipients received PGE1 intravenously (IV group) via the internal jugular vein, and 20 recipients received PGE1 intraportally (IP group) through a catheter in the inferior mesenteric vein. Data were collected for 3 weeks postoperatively. RESULTS The IP group exhibited lower initial aspartate aminotransferase and alanine aminotransferase levels compared with the IV group. However, no apparent differences were recognized in the serum albumin, total bilirubin, alkaline phosphatase, r-glutamyl transpeptidase, or prothrombin time levels between the 2 groups. Chylorous ascites were observed more frequently in the IP group. There was no difference in portal venous flow measured by Doppler sonogram between the 2 groups during the first postoperative week. CONCLUSION This study demonstrated that intraportal administration of PGE1 had a better cytoprotective effect against hepatocellular damage than intravenous administration, although it did not have additional benefits for perihepatic hemodynamics.
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Affiliation(s)
- M Shin
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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16
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Steinle JJ, Zhang Q, Thompson KE, Toutounchian J, Yates CR, Soderland C, Wang F, Stewart CF, Haik BG, Williams JS, Jackson JS, Mandrell TD, Johnson D, Wilson MW. Intra-ophthalmic artery chemotherapy triggers vascular toxicity through endothelial cell inflammation and leukostasis. Invest Ophthalmol Vis Sci 2012; 53:2439-45. [PMID: 22427570 DOI: 10.1167/iovs.12-9466] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Purpose. Super-selective intra-ophthalmic artery chemotherapy (SSIOAC) is an eye-targeted drug-delivery strategy to treat retinoblastoma, the most prevalent primary ocular malignancy in children. Unfortunately, recent clinical reports associate adverse vascular toxicities with SSIOAC using melphalan, the most commonly used chemotherapeutic. Methods. To explore reasons for the unexpected vascular toxicities, we examined the effects of melphalan, as well as carboplatin (another chemotherapeutic used with retinoblastoma), in vitro using primary human retinal endothelial cells, and in vivo using a non-human primate model, which allowed us to monitor the retina in real time during SSIOAC. Results. Both melphalan and carboplatin triggered human retinal endothelial cell migration, proliferation, apoptosis, and increased expression of adhesion proteins intracellullar adhesion molecule-1 [ICAM-1] and soluble chemotactic factors (IL-8). Melphalan increased monocytic adhesion to human retinal endothelial cells. Consistent with these in vitro findings, histopathology showed vessel wall endothelial cell changes, leukostasis, and vessel occlusion. Conclusions. These results reflect a direct interaction of chemotherapeutic drugs with both the vascular endothelium and monocytes. The vascular toxicity may be related to the pH, the pulsatile delivery, or the chemotherapeutic drugs used. Our long-term goal is to determine if changes in the drug of choice and/or delivery procedures will decrease vascular toxicity and lead to better eye-targeted treatment strategies.
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Affiliation(s)
- Jena J Steinle
- Departments of Ophthalmology, Anatomy and Neurobiology, Pharmaceutical Sciences, Radiology, and Comparative Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
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17
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Bärthel E, Rauchfuss F, Hoyer H, Habrecht O, Jandt K, Götz M, Voigt R, Heise M, Marx G, Settmacher U. Impact of stable PGI₂ analog iloprost on early graft viability after liver transplantation: a pilot study. Clin Transplant 2012; 26:E38-E47. [PMID: 21919966 DOI: 10.1111/j.1399-0012.2011.01516.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Ischemia/reperfusion injury after liver transplantation (LT) may be associated with primary graft dysfunction (PDF) or non-function. Prostaglandins were demonstrated to be beneficial in reducing ischemic injury by improving microcirculation and protecting endothelial cells. The aim of this study was to analyze the effect of the continuously administered prostaglandin I(2) analog iloprost on allograft function after LT. METHODS Eighty patients were prospectively randomized and assigned to two groups. Patients in the treatment group received iloprost for seven d after transplantation, and those in the control group did not. The primary end point was graft dysfunction. RESULTS The incidence of PDF was 20% (n = 8) in the control group and 5% (n = 2) in the treatment group, respectively (p = 0.087). Four patients in the control group underwent re-transplantation for initial non-function (INF). There was no evidence for INF in the treatment group. Iloprost was associated with improved allograft function. Clinical course and outcome were comparable. CONCLUSIONS We suggest iloprost to be beneficial for early post-transplant liver function. If the rate of PDF can be significantly reduced with this treatment concept, it should be analyzed in a larger number of patients (ISRCTN95672167).
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Affiliation(s)
- Erik Bärthel
- Department of General, Visceral and Vascular Surgery, Friedrich-Schiller-University, Jena, Germany.
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Köhler D, Birk P, König K, Straub A, Eldh T, Morote-Garcia JC, Rosenberger P. Phosphorylation of vasodilator-stimulated phosphoprotein (VASP) dampens hepatic ischemia-reperfusion injury. PLoS One 2011; 6:e29494. [PMID: 22216296 PMCID: PMC3245274 DOI: 10.1371/journal.pone.0029494] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2011] [Accepted: 11/29/2011] [Indexed: 01/29/2023] Open
Abstract
Recent work has demonstrated that the formation of platelet neutrophil complexes (PNCs) affects inflammatory tissue injury. Vasodilator-stimulated phosphoprotein (VASP) is crucially involved into the control of PNC formation and myocardial reperfusion injury. Given the clinical importance of hepatic IR injury we pursued the role of VASP during hepatic ischemia followed by reperfusion. We report here that VASP−/− animals demonstrate reduced hepatic IR injury compared to wildtype (WT) controls. This correlated with serum levels of lactate dehydrogenase (LDH), aspartate (AST) and alanine (ALT) aminotransferase and the presence of PNCs within ischemic hepatic tissue and could be confirmed using repression of VASP through siRNA. In studies employing bone marrow chimeric mice we identified hematopoietic VASP to be of crucial importance for the extent of hepatic injury. Phosphorylation of VASP on Ser153 through Prostaglandin E1 or on Ser235 through atrial natriuretic peptide resulted in a significant reduction of hepatic IR injury. This was associated with a reduced presence of PNCs in ischemic hepatic tissue. Taken together, these studies identified VASP and VASP phosphorylation as crucial target for future hepatoprotective strategies.
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Affiliation(s)
- David Köhler
- Department of Anesthesiology and Intensive Care Medicine, University Hospital, Tübingen, Germany
| | - Philipp Birk
- Department of Anesthesiology and Intensive Care Medicine, University Hospital, Tübingen, Germany
| | - Klemens König
- Clinic of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt am Main, Johann Wolfgang Goethe University, Frankfurt, Germany
| | - Andreas Straub
- Department of Anesthesiology and Intensive Care Medicine, University Hospital, Tübingen, Germany
| | - Therese Eldh
- Department of Radiation Oncology, University Hospital, Tübingen, Germany
| | - Julio C. Morote-Garcia
- Department of Anesthesiology and Intensive Care Medicine, University Hospital, Tübingen, Germany
| | - Peter Rosenberger
- Department of Anesthesiology and Intensive Care Medicine, University Hospital, Tübingen, Germany
- Clinic of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt am Main, Johann Wolfgang Goethe University, Frankfurt, Germany
- * E-mail:
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Ischemic preconditioning-like effect of polyunsaturated fatty acid-rich diet on hepatic ischemia/reperfusion injury. J Gastrointest Surg 2011; 15:1679-88. [PMID: 21826546 DOI: 10.1007/s11605-011-1648-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2011] [Accepted: 07/26/2011] [Indexed: 01/31/2023]
Abstract
AIM The aim of this study was to investigate a possible preconditioning effect of oral diet enriched with polyunsaturated fatty acids (PUFAs) on liver ischemia/reperfusion (I/R) injuries. METHODS Wistar male rats were fed a standard diet or polyunsaturated fatty acid-rich diet (PRD) enriched with (GII) or without (GIII) ω-3 PUFA. Rats were submitted to partial liver ischemia during 1 h and evaluated in pre- and post-I/R conditions. In pre-I/R condition, livers were collected for determination of fatty acid composition, liver mitochondrial function, malondialdehyde (MDA) content, and histological analysis. Four hours after liver reperfusion serum activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), serum levels of tumor necrosis factor-alpha, interleukin-6, interleukin-10, and prostaglandin-E2, liver mitochondrial function, MDA content, and histology were evaluated. RESULTS In the pre-I/R condition, GII and GIII groups had an increase on PUFA content and exhibited slight increased macrosteatosis and microsteatosis in the liver. After 4 h of reperfusion, PRD-fed rats showed a marked decrease on steatosis, diminished necrosis, an increase in MDA formation, and mitochondrial uncoupling. We also observed a marked decrease in plasma levels of cytokines and ALT and AST activities in post-I/R condition in PRD groups. CONCLUSION In this experimental model in the rat, PRD has a preconditioning effect protecting the liver from I/R injury and should be object of future clinical studies.
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Abstract
Warm hepatic ischemia-reperfusion injury is a significant medical problem in many clinical conditions such as liver transplantation, hepatic surgery for tumor excision, trauma and hepatic failure after hemorrhagic shock. Partial or, mostly, total interruption of hepatic blood flow is often necessary when liver surgery is performed. This interruption of blood flow is termed "warm ischemia" and upon revascularization, when molecular oxygen is reintroduced, the organ undergoes a process called "reperfusion injury" that causes deterioration of organ function. Ischemia reperfusion results in cellular damage and tissue injury associated with a complex series of events. Pathophysiological mechanisms leading to tissue injury following ischemia-reperfusion will be discussed and therapies targeted to reduce liver damage will be summarized within this review.
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Affiliation(s)
- Serdar Dogan
- Department of Biochemistry, Akdeniz University School of Medicine, Antalya, Turkey
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Hara Y, Akamatsu Y, Kobayashi Y, Iwane T, Satomi S. Perfusion Using Oxygenated Buffer Containing Prostaglandin E1 before Cold Preservation Prevents Warm Ischemia-Reperfusion Injury in Liver Grafts from Non-Heart-Beating Donors. Transplant Proc 2010; 42:3973-6. [DOI: 10.1016/j.transproceed.2010.09.085] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2010] [Accepted: 09/22/2010] [Indexed: 11/16/2022]
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Fang L, Du SY, Zhao HC, Yao SK. Role of oxidative stress in the pathogenesis of chronic hepatic injury induced by ethanol and carbon tetrachloride in rats. Shijie Huaren Xiaohua Zazhi 2010; 18:234. [DOI: 10.11569/wcjd.v18.i3.234] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Vollmar B, Menger MD. The hepatic microcirculation: mechanistic contributions and therapeutic targets in liver injury and repair. Physiol Rev 2009; 89:1269-339. [PMID: 19789382 DOI: 10.1152/physrev.00027.2008] [Citation(s) in RCA: 372] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The complex functions of the liver in biosynthesis, metabolism, clearance, and host defense are tightly dependent on an adequate microcirculation. To guarantee hepatic homeostasis, this requires not only a sufficient nutritive perfusion and oxygen supply, but also a balanced vasomotor control and an appropriate cell-cell communication. Deteriorations of the hepatic homeostasis, as observed in ischemia/reperfusion, cold preservation and transplantation, septic organ failure, and hepatic resection-induced hyperperfusion, are associated with a high morbidity and mortality. During the last two decades, experimental studies have demonstrated that microcirculatory disorders are determinants for organ failure in these disease states. Disorders include 1) a dysregulation of the vasomotor control with a deterioration of the endothelin-nitric oxide balance, an arterial and sinusoidal constriction, and a shutdown of the microcirculation as well as 2) an overwhelming inflammatory response with microvascular leukocyte accumulation, platelet adherence, and Kupffer cell activation. Within the sequelae of events, proinflammatory mediators, such as reactive oxygen species and tumor necrosis factor-alpha, are the key players, causing the microvascular dysfunction and perfusion failure. This review covers the morphological and functional characterization of the hepatic microcirculation, the mechanistic contributions in surgical disease states, and the therapeutic targets to attenuate tissue injury and organ dysfunction. It also indicates future directions to translate the knowledge achieved from experimental studies into clinical practice. By this, the use of the recently introduced techniques to monitor the hepatic microcirculation in humans, such as near-infrared spectroscopy or orthogonal polarized spectral imaging, may allow an early initiation of treatment, which should benefit the final outcome of these critically ill patients.
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Affiliation(s)
- Brigitte Vollmar
- Institute for Experimental Surgery, University of Rostock, Rostock, Germany.
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Ishibe A, Togo S, Kumamoto T, Watanabe K, Takahashi T, Shimizu T, Makino H, Matsuo K, Kubota T, Nagashima Y, Shimada H. Prostaglandin E1 prevents liver failure after excessive hepatectomy in the rat by up-regulating Cyclin C, Cyclin D1, and Bclxl. Wound Repair Regen 2009; 17:62-70. [PMID: 19152652 DOI: 10.1111/j.1524-475x.2008.00442.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Prostaglandin E1 (PGE1) has wide-ranging effects on cytoprotection and may play a role in preventing liver failure following excessive hepatectomy. We examined the effect of PGE1 on hepatocyte apoptosis and liver regeneration after 95% hepatectomy in a rat model. PGE1 or vehicle was intravenously administered 30 minutes before and during hepatectomy. The extent of hepatocyte injury was evaluated by serum alanine aminotransferase and aspartate aminotransferase levels. To evaluate hepatocyte apoptosis and liver regeneration, terminal deoxynucleotidyl transferase dUTP nick end labeling staining and Ki67 labeling were performed. The expression levels of Bcl-xL, Bcl-2, Bax, Cyclin C, Cyclin D1, Cyclin E, p21, transforming growth factor-beta, plasminogen activator inhibitor-1, and glyceraldehyde-2-phosphate dehydrogenase mRNA were also examined by reverse transcription-polymerase chain reaction. Survival was improved in the PGE1 group (26.6%), whereas all rats in the vehicle group died within 60 hours. PGE1 significantly suppressed the release of alanine aminotransferase and aspartate aminotransferase at 12 hours postoperatively. Pretreatment with PGE1 significantly increased the Ki67-positive cell count and decreased the terminal deoxynucleotidyl transferase dUTP nick end labeling positive cell count after hepatectomy, and also significantly increased the expression levels of Bcl-xL, Cyclin C, and Cyclin D1. Our results suggest that pretreatment with PGE1 may increase survival following hepatectomy by salvaging the remaining liver tissue, which it does by inhibiting apoptosis and stimulating hepatocyte proliferation.
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Affiliation(s)
- Atsushi Ishibe
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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Kim E, Hong JP. Decreasing the Expression of LFA-1 and ICAM-1 as the Major Mechanism for the Protective Effect of Erythropoietin on Ischemia-Reperfusion Injury. Plast Reconstr Surg 2008. [DOI: 10.1097/prs.0b013e31817d66e6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Abstract
Linoleic and alpha-linolenic acids are the fatty acids designated as "essential" since they are not synthesized by mammalian cells and must be provided in the diet. The recent dietary shift towards the consumption of n-6 (omega-6) at the expense of n-3 (omega-3) polyunsaturated fatty acids (PUFAs) is thought to be a primary cause of many diseases related to the Western diet. The body converts linoleic acid to arachidonic acid and derives eicosapentaenoic acid from alpha-linolenic acid. Ideally the effects of these fatty acids and their eicosanoid derivatives are tailored to the specific biological needs of the body. The balance between n-3 and n-6 PUFAs is essential for metabolism and maintenance of the functions of both classes. The availability of n-3 long chain PUFAs plays a major role in regulating both fat accumulation and its elimination by the liver. Derangement of hepatic n-6:n-3 PUFA ratio impacts on the histological pattern of fatty liver through modulation of the amount of intrahepatic lipids. Moreover, the influence of PUFAs and their eicosanoid products on hepatic microcirculation and ischemia/reperfusion injury has been demonstrated in many studies. This concise review article will focus on the role of PUFAs and eicosanoids in hepatic steatosis, microcirculation and ischemia/reperfusion injury.
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Affiliation(s)
- Ashraf Mohammad El-Badry
- Swiss HPB (Hepato-Pancreatico-Biliary) Centre, Department of Visceral and Transplant Surgery, University Hospital Zurich, Ramistrasse 100, CH-8091, Zurich, Switzerland
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Togo S, Chen H, Takahashi T, Kubota T, Matsuo K, Morioka D, Watanabe K, Yamamoto H, Nagashima Y, Shimada H. Prostaglandin E1 improves survival rate after 95% hepatectomy in rats. J Surg Res 2007; 146:66-72. [PMID: 17599359 DOI: 10.1016/j.jss.2007.05.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2007] [Indexed: 12/31/2022]
Abstract
BACKGROUND/AIM Prostaglandin E1 (PGE1) has a wide-ranging effect on cytoprotection. Overproduction of heat shock protein 70 (HSP70) in the liver protects hepatocytes under various pathologic conditions. In this study, we examined the effect of a nontoxic HSP-inducer, PGE1, on acute liver failure after 95% hepatectomy in rats. METHODS PGE1 or vehicle was intravenously administered to rats 30 min before and during hepatectomy. RESULTS Nine of 30 rats pretreated with PGE1 survived, whereas all 20 rats pretreated with vehicle died within 96 h after operation. During the 24-h postoperative period, PGE1 significantly suppressed the release of alanine aminotransferase and elevation of hyaluronic acid. Histological examination showed that the vacuolized hepatocytes and round hepatocytes with pyknotic nuclei are frequently seen in rats pretreated with vehicle, whereas active regeneration is seen in rats pretreated with PGE1. During the first 24 h after surgery, HSP70 induction was absent in the residual livers of vehicle-treated rats. In contrast, PGE1 stimulated the HSP accumulation within 24 h, and viable hepatocytes contained abundant HSP70 in their nuclei. CONCLUSION Our results suggest that PGE1 may prevent acute liver failure after massive hepatectomy, at least in part, by enhancing HSP70 production in the residual liver.
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Affiliation(s)
- Shinji Togo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
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Abstract
Liver surgery is associated with many factors, which may affect outcome. Preoperative assessment of patient's general condition, resectability, and liver reserve are paramount for success. The Child-Pugh score and other scoring systems only partially enables to assess the risk associated with liver surgery. The presence of portal hypertension per se is a major risk factor for hepatectomy. Intraoperatively, any attempts should be made to minimize blood loss. Low central venous pressure and inflow occlusion best prevent bleeding. Ischemic preconditioning and intermittent clamping are routinely applied in many centers to protect against long periods of ischemia, although the mechanisms of protection remain unclear. In this review we describe recent advances in activated pathways associated with protection against ischemia. Postoperatively, the best factor impacting on outcome probably resides in experienced medical care particularly in the intensive care setting. Currently, no drug or gene therapy approaches has reached the clinic. The future relies on new insight into mechanisms of ischemia-reperfusion injury.
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Affiliation(s)
- Katarzyna Furrer
- Department of Visceral and Transplantation Surgery, University Hospital of Zürich, 8091-Zürich, Switzerland
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Hafez T, Moussa M, Nesim I, Baligh N, Davidson B, Abdul-Hadi A. The effect of intraportal prostaglandin E1 on adhesion molecule expression, inflammatory modulator function, and histology in canine hepatic ischemia/reperfusion injury. J Surg Res 2006; 138:88-99. [PMID: 17174338 DOI: 10.1016/j.jss.2006.05.009] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2006] [Revised: 04/03/2006] [Accepted: 05/01/2006] [Indexed: 01/11/2023]
Abstract
BACKGROUND Prostaglandin E1 (PGE1) is known to protect the liver from I/R, however, the mechanism of cytoprotection is not well understood. This study investigates the effect of intraportal infusion of PGE1 in a warm liver ischemia/reperfusion (I/R) model on cytokines, adhesion molecules and liver structure. MATERIALS AND METHODS Twenty dogs underwent laparotomy under general anesthesia. PGE1 (0.02 microg\kg\min) was perfused through the portal vein in the PGE1 group (n = 10), or a similar volume of Ringer's solution in the control group (n = 10) for 15 min. Liver ischemia was induced by hepatic artery and portal vein occlusion and PGE1 was infused via the portal vein for 60 min. The occlusion was released and PGE1 infusion recommenced for 30 min. Blood and liver biopsies were sampled at baseline, 60 min ischemia, and 30 min reperfusion and assessed for transaminases, cytokines, adhesion molecules, and electron microscopy. RESULTS PGE1 infusion significantly reduced transaminases TNF-alpha, sICAM-1, sP-selectin, and sE-selectin on ischemia and reperfusion. PGE1 reduced hepatocytic degeneration, portal and central ICAM-1 expression, central and sinusoidal VCAM-1 expression, portal and central P-selectin expression, and portal and sinusoidal E-selectin expression on reperfusion. CONCLUSION Intraportal PGE1 infusion reduced I/R injury and was associated with down-regulation of ICAM-1, VCAM-1, P-selectin, and E-selectin on reperfusion.
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Affiliation(s)
- Tariq Hafez
- Department of Surgery, Royal Free and University College Medical School, University College London, London, United Kingdom
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Tanaka K, Shimada H, Togo S, Nagano Y, Endo I, Sekido H. Outcome using hemihepatic vascular occlusion versus the pringle maneuver in resections limited to one hepatic section or less. J Gastrointest Surg 2006; 10:980-6. [PMID: 16843868 DOI: 10.1016/j.gassur.2006.01.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2005] [Accepted: 01/05/2006] [Indexed: 01/31/2023]
Abstract
Consensus is lacking concerning how to manage afferent vessels during hepatectomy, particularly as to the Pringle maneuver vs. selective hemihepatic clamping. Data for 81 hepatocellular carcinoma patients with chronic hepatitis or liver cirrhosis whose liver resection was limited to one section or less, including intraoperative data and postoperative liver function data, were analyzed retrospectively to compare two strategies. No significant differences of intraoperative data or postoperative clinical course were seen between the two groups, even in patients with chronic hepatitis or liver cirrhosis whose postoperative deterioration of liver function could be expected to be more than patients with a normal liver. The difference was evident only in serum alanine aminotransferase level on postoperative day 10 (mean +/- SEM, 64.5 +/- 5.1 IU in the Pringle group vs. 51.6 +/- 4.4 IU in the selective clamping group; P < 0.05). During liver resection limited to one section or less, even with underlying chronic hepatitis or cirrhosis, intermittent use of the Pringle maneuver preserved liver function to the same extent as selective clamping.
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Affiliation(s)
- Kuniya Tanaka
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
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Tauber S, Menger MD, Lehr HA. Microvascular in vivo assessment of reperfusion injury: significance of prostaglandin E1 and I2 in postischemic “no-reflow” and “reflow-paradox”. J Surg Res 2004; 120:1-11. [PMID: 15172184 DOI: 10.1016/s0022-4804(03)00332-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2002] [Indexed: 11/16/2022]
Abstract
BACKGROUND Microvascular ischemia-reperfusion (I/R) injury is characterized by failure of capillary perfusion ("no-reflow") and reoxygenation-associated phenomena ("reflow-paradox"), including activation of leukocyte-endothelium interaction with cytotoxic mediator-induced loss of endothelial integrity. The objectives of this study were to elucidate the impact of both prostaglandins E(1) (PGE(1)) and I(2) (PGI(2)) in microvascular reperfusion injury, with special focus on the distinct pathophysiology of no-reflow- and reflow-paradox phenomena. MATERIALS AND METHODS By use of the hamster dorsal skinfold preparation and in vivo fluorescence microscopy, the microcirculation of a striated skin muscle was assessed before 4 h of pressure-induced ischemia and 0.5, 2, and 24 h after onset of reperfusion. RESULTS I/R was characterized by enhanced leukocyte-endothelium interaction in postcapillary venules, increase of macromolecular leakage, and reduction of functional capillary perfusion (P < 0.05). Intravenous 2-h infusion of PGE(1), starting with onset of reperfusion, reduced leukocyte adhesion and macromolecular leakage in postcapillary venules during early reperfusion (P < 0.05), while 6-h infusion, given during ischemia and early reperfusion, showed no significant effects. PGI(2) infusion also attenuated postischemic leukocyte adhesion, which was significant by a 6-h prolonged administration (P < 0.05), but did not influence the increase of microvascular permeability. Both prostaglandins were unable to prevent the postischemic failure of capillary perfusion (no-reflow). CONCLUSIONS Both prostaglandins did not significantly influence postischemic no-reflow phenomena, but appeared as potent inhibitors of reflow-paradox under the experimental circumstances of this study.
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Affiliation(s)
- Stefan Tauber
- Institute for Surgical Research, University of Munich, D-81377 Munich, Germany.
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Kawaguchi A, Ohmori M, Fujimura A. Partial protective effect of Y-27632, a Rho kinase inhibitor, against hepatic ischemia–reperfusion injury in rats. Eur J Pharmacol 2004; 493:167-71. [PMID: 15189778 DOI: 10.1016/j.ejphar.2004.04.023] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2004] [Revised: 04/07/2004] [Accepted: 04/09/2004] [Indexed: 10/26/2022]
Abstract
(+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)-cyclohexanecarboxamide dihydrochloride (Y-27632), a Rho kinase inhibitor, has a suppressive effect on the functions of polymorphonuclear leukocytes. In this study, the influence of Y-27632 on ischemia-reperfusion injury of the liver was examined in rats. Y-27632 (3 mg/kg) or vehicle alone was intravenously injected into rats 60 min before occlusion. Blood samples were obtained for 48 h after reperfusion. At the end of the experiment, the hepatic content of myeloperoxidase, which reflects the number of polymorphonuclear leukocytes in liver tissues, was determined. The increases in serum hepatic aminotransferases and inflammatory cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6] after reperfusion were partially, but significantly, inhibited by Y-27632. The increased hepatic myeloperoxidase content was significantly lowered by Y-27632. These results suggest that Y-27632 has a partial protective effect against hepatic ischemia-reperfusion injury through the suppression of polymorphonuclear leukocytes and inflammatory cytokines.
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Affiliation(s)
- Atsuhiro Kawaguchi
- Department of Clinical Pharmacology, Jichi Medical School, Tochigi 329-0498, Japan
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Takahashi HK, Iwagaki H, Tamura R, Xue D, Sano M, Mori S, Yoshino T, Tanaka N, Nishibori M. Unique regulation profile of prostaglandin e1 on adhesion molecule expression and cytokine production in human peripheral blood mononuclear cells. J Pharmacol Exp Ther 2003; 307:1188-95. [PMID: 14561849 DOI: 10.1124/jpet.103.056432] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
In the present study, we examined the effects of prostaglandin E1 (PGE1) on the expression of intercellular adhesion molecule (ICAM)-1, B7.1, B7.2, CD40, and CD40 ligand (CD40L) on peripheral blood mononuclear cells (PBMC) using fluorescence-activated cell sorting analysis as well as its effects on cytokine production using enzyme-linked immunosorbent assay. Whereas no inhibitor of spontaneous expression of adhesion molecules was reported, we found that PGE1 inhibited spontaneous ICAM-1, B7.2, and CD40 expression on monocytes in a concentration-dependent manner but had no effect on the expression of B7.1 and CD40L. Although interleukin (IL)-18 induced the expression of ICAM-1, B7.2, CD40, and CD40L, PGE1 prevented IL-18-induced expression of ICAM-1, B7.2, and CD40. We examined the involvement of five subtypes of PGE1 receptors (IP, EP1, EP2, EP3, and EP4) in the effect of PGE1 on the expression of these adhesion molecules using subtype-specific agonists. Among EP receptor agonists, EP2 and EP4 receptor agonists inhibited IL-18-elicited ICAM-1, B7.2, and CD40 expression. ONO-1301 (IP receptor agonist) prevented the expression of ICAM-1, B7.2, and CD40 regardless of the presence of IL-18 with the same potency as PGE1. The effect of a combination of ONO-1301 and 11-deoxy (D)-PGE1 (EP2/EP4 receptor agonist) on ICAM-1, B7.2, and CD40 expression mimicked that of PGE1. Moreover, PGE1 inhibited the production of IL-12 and interferon-gamma in PBMC in the presence and absence of IL-18, whereas PGE1 induced IL-10 production. In conclusion, IP receptor and EP2/EP4 receptor play an important role in the action of PGE1 on the expression of adhesion molecules on monocytes and cytokine production.
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Affiliation(s)
- Hideo Kohka Takahashi
- Department of Pharmacology, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan
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Ohira H, Abe K, Yokokawa J, Takiguchi J, Rai T, Shishido S, Sato Y. Adhesion molecules and CXC chemokines in endotoxin-induced liver injury. Fukushima J Med Sci 2003; 49:1-13. [PMID: 14603947 DOI: 10.5387/fms.49.1] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Interactions between leukocytes and sinusoidal endothelial cells are known to be involved in the pathogenesis of acute liver injury. Various adhesion molecules and chemokines play key roles in these cell-to-cell interactions, and the expression of these adhesion molecules and the production of chemokines are regulated by inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and interferon-gamma (IFN-gamma). We have shown that the expression of intercellular adhesion molecule-1 (ICAM-1) on cultured rat sinusoidal endothelial cells stimulated with TNF-alpha increases in a dose-dependent manner. The number of neutrophils that adhered to sinusoidal endothelial cells pretreated with TNF-alpha also increased in a dose-dependent manner and significantly decreased upon incubation with an anti-ICAM-1 antibody. In endotoxin-induced rat liver injury, the number of neutrophils infiltrating the sinusoids increased after serum TNF-alpha, macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (CINC) reached their peak levels. In addition, the level of ICAM-1 expression on sinusoidal endothelial cells greatly increased from 8 h after exposure to endotoxin, and these cells were adhered to neutrophils that expressed both LFA-1 and Mac-1. Moreover, lipo-prostaglandin E1 (PGE1) reduced the extent of liver injury, and also reduced the number of neutrophils that infiltrated the liver, was reduced the production of MIP-2 and CINC, but not that of TNF-alpha, in rats injected with endotoxin.
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Affiliation(s)
- Hiromasa Ohira
- Department of Internal Medicine II, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
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Kato T, Sato T, Kurokawa T, Nanjo H, Asanuma Y, Koyama K. Efficacy of continuous infusion of prostaglandin E1 through the superior mesenteric artery against ischemic liver cell necrosis after hepatic artery occlusion. Transplantation 2003; 76:1340-5. [PMID: 14627913 DOI: 10.1097/01.tp.0000092526.60205.4f] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Hepatic artery occlusion (HAO) can cause severe ischemic liver injury, especially after an interruption of collateral circulation after extensive hepatobiliary surgery. To minimize a decrease in oxygen delivery after HAO, a continuous infusion of prostaglandin (PG)E1 through the superior mesenteric artery (SMA) was studied in comparison with other infusion routes. METHODS Twenty-four pigs were assigned to four groups: HAO without PGE1 (control group); HAO with PGE1 (0.02 microg/kg/min, continuously) through the jugular vein (intravenous group); HAO with PGE1 through the portal vein (PV group); and HAO with PGE1 through the SMA (SMA group). PV flow, hepatic oxygen delivery, and serum aspartate aminotransferase were measured after infusion. In addition, 72-hr survival rates were observed, and histologic examination of liver specimens was performed. RESULTS PGE1 infusion through the SMA seems to affect PV flow and elevate the oxygen content of portal blood, whereas other routes of administration do not. The reduction of hepatic oxygen delivery after HAO was 51% in the control group, 46% in the intravenous group, and 49% in the PV group, whereas it was limited to 13% in the SMA group. Serum aspartate aminotransferase values 24 hr after HAO were lowest in the SMA group, which was statistically significant, as confirmed by histology. The survival rate of animals was 100% in the SMA group and 33% in the other three groups. CONCLUSION These findings indicate that continuous PGE1 infusion through the SMA may prove useful in clinical settings to prevent liver damage after HAO.
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Affiliation(s)
- Takeshi Kato
- Department of Surgery, Akita University School of Medicine, Akita, Japan
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Hossain MA, Izuishi K, Maeta H. Effect of short-term administration of prostaglandin E1 on viability after ischemia/reperfusion injury with extended hepatectomy in cirrhotic rat liver. World J Surg 2003; 27:1155-60. [PMID: 12925901 DOI: 10.1007/s00268-003-6914-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
The cytoprotective effect of prostaglandin E(1) (PGE(1)) has been demonstrated experimentally and clinically against hepatic ischemia and reperfusion injury and against the effects of partial hepatectomy in both individual and combined models of noncirrhotic livers. Cirrhotic livers are more vulnerable to ischemia/reperfusion injury during hepatectomy than are noncirrhotic livers, and postoperative malfunctioning complicates life with multiple organ failure. Cirrhotic livers with tumors have mostly been treated conservatively because extended hepatectomy with induced ischemia during surgery is impossible. The purpose of our study was to document postoperative surgical adaptation in inoperable cases with improved survival after extended hepatectomy in a rat model of cirrhosis treated by PGE(1). Cirrhosis was induced by intraperitoneal injections of 1% dimethylnitrosamine. The liver was subjected to 15 minutes of total ischemia by occluding the hepatoduodenal ligament. Hepatectomy was performed during ischemia. Pretreatment with PGE(1) (0.4 microg/kg/min) (or without it in the controls) was given for 15 minutes by intravenous infusion prior to inducing ischemia and during reperfusion. Portal venous flow (PVF) and liver tissue blood flow (LTBF) were measured during reperfusion. At the end of 60 minutes of reperfusion, venous blood was collected for liver function tests. The animals were followed up regarding survival for 48 hours. The PVF and LTBF were significantly improved in the PGE(1) group. The blood chemical analysis indicated that PGE(1) significantly suppressed posthepatectomy liver dysfunction. Most importantly, PGE(1) treatment markedly improved the survival rate, from 42% in the controls to 75% in the test animals at 24 hours after hepatectomy and from 17% in the controls to 58% in the test animals at 48 hours. We concluded that short-term administration of PGE(1) makes extensive hepatectomy possible under ischemic conditions in cirrhotic livers.
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Affiliation(s)
- Mohammad Akram Hossain
- First Department of Surgery, Kagawa Medical University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
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Uchida K, Tateda T, Takagi S. Hypothetical mechanism of prostaglandin E1-induced bronchoconstriction. Med Hypotheses 2003; 61:378-84. [PMID: 12944106 DOI: 10.1016/s0306-9877(03)00174-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
In general, prostaglandin E1 (PGE1) is thought to relax smooth muscles in the airway and to inhibit muscle constriction. We hypothesized that, under the specific conditions, PGE1 induces bronchoconstriction, resulting in the promotion of inflammation. Examples of the specific conditions where this mechanism may occur include cases where patient who are susceptible to inflammation receive a continuous infusion of PGE1 during induced hypotension or during treatment for intraoperatively abnormal hypertension.
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Affiliation(s)
- K Uchida
- Department of Anesthesiology, St. Marianna University School of Medicine, 2-16-1 Sugao, Kawasaki 216-8511, Japan.
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Marchesi S, Pasqualini L, Lombardini R, Vaudo G, Lupattelli G, Pirro M, Schillaci G, Mannarino E. Prostaglandin E1 improves endothelial function in critical limb ischemia. J Cardiovasc Pharmacol 2003; 41:249-53. [PMID: 12548086 DOI: 10.1097/00005344-200302000-00014] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Prostaglandin E1 (PGE1) may relieve rest pain and heal ulcers in critical limb ischemia, but its mechanism of action is still incompletely understood. To investigate the effects of PGE1 treatment on endothelial function evaluated as brachial artery flow-mediated vasodilation (FMV) and on soluble adhesion molecule plasma levels (vascular adhesion molecule-1 [sVCAM-1] and intercellular adhesion molecule-1 [sICAM-1]), 12 patients with critical limb ischemia were treated with daily PGE IV infusion (alprostadil 60 microg) for 2 weeks. FMV and plasma sICAM-1 and sVCAM-1 concentrations were determined at baseline, after the first infusion, and after 1 and 2 weeks. Compared with 30 healthy control subjects, patients had higher baseline sVCAM-1 (2.402 +/- 296 ng/ml vs 972 +/- 117 ng/ml) and sICAM-1 levels (464 +/- 51 ng/ml vs 206 +/- 37 ng/ml, both p < 0.05) and lower FMV (1.0 +/- 1.1% vs 5.6 +/- 1.6%, p < 0.05). sICAM-1 concentration progressively decreased with treatment (from 464 +/- 51 ng/ml to 326 +/- 56 ng/ml, 288 +/- 42 ng/ml, and 279 +/- 44 ng/ml after the first dose and, respectively, after 1 and 2 weeks; all p < 0.05). sVCAM-1 showed a reduction after 2 weeks (from 2.402 +/- 296 ng/ml to 1.916 +/- 176 ng/ml; p < 0.05). FMV improved after 1 and 2 weeks (from 1.0 +/- 1.1% to 3.1 +/- 0.6% and 5.2 +/- 2.1%, both p < 0.05). In conclusion, treatment with PGE1 determines a significant improvement in endothelial function in patients with critical limb ischemia.
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Affiliation(s)
- Simona Marchesi
- Unit of Internal Medicine, Angiology and Arteriosclerosis, University of Perugia Medical School, via Brunacci Brunamonti, 51 IT-06122 Perugia, Italy.
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Morioka D, Kubota T, Sekido H, Matsuo K, Saito S, Ichikawa Y, Endo I, Togo S, Shimada H. Prostaglandin E1 improved the function of transplanted fatty liver in a rat reduced-size-liver transplantation model under conditions of permissible cold preservation. Liver Transpl 2003; 9:79-86. [PMID: 12514777 DOI: 10.1053/jlts.2003.36845] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The aim of this study was to determine whether the minimum necessary volume of a moderate fatty liver graft was similar to the normal liver volume and to elucidate means for improving the function of the transplanted fatty liver if it were inferior in volume to a normal liver under conditions of permissible cold preservation. Nine-week-old male Wistar rats were used. Normal rat chow was fed to the normal liver group, and fat-enriched rat chow was fed to the fatty liver group for 4 weeks to induce a moderately fatty liver. Liver transplantation with various volumes of reduced-size grafts, including whole liver graft (100%LT), 70% volume graft (70%LT), and 30% volume graft (30%LT), was performed with both groups of rats as donors. All procedures were performed under the conditions of 2-hour cold preservation. All rats with an implanted normal liver were surviving at 7 days after the operation regardless of the graft volume (100%LT, 5 of 5; 70%LT, 5 of 5; 30%LT, 5/5). In contrast, the survival rates decreased according to the graft volume in rats implanted with fatty livers (100%LT, 8 of 8; 70%LT, 5 of 8; 30%LT, 2/8). To improve the survival of 30%LT with fatty liver, we employed two potent inhibitors of ischemia-reperfusion injury: FK506 and prostaglandin E1. Though FK506 had no advantageous effect, prostaglandin E1 significantly improved the survival rate and diminished serum levels of alanine aminotransferase and hyaluronic acid. In conclusion, the volume of graft necessary for successful transplantation is larger in fatty livers than in normal livers in permissible cold preservation. Also, prostaglandin E1 protects grafts against ischemia-reperfusion injury and improves the functioning of a transplanted fatty liver.
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Affiliation(s)
- Daisuke Morioka
- Second Department of Surgery, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
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Kotani N, Hashimoto H, Kushikata T, Yoshida H, Muraoka M, Takahashi S, Matsuki A. Intraoperative prostaglandin E1 improves antimicrobial and inflammatory responses in alveolar immune cells. Crit Care Med 2001; 29:1943-9. [PMID: 11588457 DOI: 10.1097/00003246-200110000-00016] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
OBJECTIVE Anesthesia and surgery decrease antimicrobial and increase proinflammatory functions of alveolar immune cells. Thus, anti-inflammatory agents that do not further suppress antimicrobial functions are required. We tested the hypothesis that intraoperative prostaglandin E1 (PGE1) suppresses proinflammatory responses and prevents the reduction in antimicrobial responses of alveolar immune cells. DESIGN Prospective, randomized, controlled, double-blind study. SETTING University hospital. PATIENTS A total of 40 patients undergoing elective orthopedic surgery under propofol/fentanyl anesthesia. INTERVENTION In double-blind fashion, the patients received PGE1 from the beginning to the end of surgery (PGE1 group, n = 20) or nothing (control group, n = 20). METHODS AND MAIN RESULTS Alveolar immune cells were harvested by bronchoalveolar lavage immediately after induction of anesthesia; 2, 4, and 6 hrs after induction of anesthesia; and at the end of surgery. We measured opsonized and nonopsonized phagocytosis. Microbicidal activity was evaluated to directly kill Listeria monocytogenes in alveolar macrophages. Finally, we determined the expression of proinflammatory cytokines including interleukin (IL)-1beta, IL-8, interferon-gamma, and tumor necrosis factor-alpha, and that of anti-inflammatory cytokines (IL-4 and IL-10) by semiquantitative polymerase chain reaction. Nonopsonized and opsonized phagocytosis and microbicidal activity of alveolar macrophages decreased and the expression of genes for all pro- and anti-inflammatory cytokines increased significantly over time in both groups. Starting 2-4 hrs after induction of anesthesia, the increases in gene expression of proinflammatory cytokines were 1.5-3 times smaller in the PGE1 than in the control group. Starting 6 hrs after anesthesia, the increase in gene expression of IL-10 was 1.5-3 times greater in the PGE1 than in the control group. Intraoperative decreases in phagocytic and microbial activities were the same in the two groups. CONCLUSION Intraoperative PGE1 not only suppressed proinflammatory responses, but also protected antimicrobial functions of alveolar macrophages, possibly because PGE1 is mostly inactivated in the pulmonary intravascular space. Our results suggest that intraoperative PGE1 protects the pulmonary immune defense in alveolar immune cells.
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Affiliation(s)
- N Kotani
- Department of Anesthesiology, University of Hirosaki School of Medicine, Hirosaki, Japan.
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Sato T, Yasui O, Kurokawa T, Asanuma Y, Koyama K. Appraisal of intra-arterial infusion of prostaglandin E1 in patients undergoing major hepatic resection report of four cases. TOHOKU J EXP MED 2001; 195:125-33. [PMID: 11846208 DOI: 10.1620/tjem.195.125] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
In order to reduce risk for postoperative acute liver failure, prostaglandin E1 (PGE1) was administered either from the hepatic artery (HA) or the superior mesenteric artery (SMA) in four high-risk cases undergoing major hepatic resection. Two cases were subjected to HA PGE1 infusion for 3 or 4 days after surgery at a rate of 0.01 microg/kg/min. Both patients had hepatocellular carcinoma (HCC) associated with chronic hepatitis, and ICG R15 was 17.6% and 14.5%, respectively. Right hemihepatectomy and extended right hemihepatectomy were performed. Serum total bilirubin (T. Bil.) peak value was 2.2 mg/100 ml in Case 1 and 2.1 mg/100 ml in Case 2. In Case 1, decreased bile flow was observed immediately after cessation of PGE1. The other two cases were subjected to SMA PGE1 infusion for 5 or 6 days after surgery at the same rate. In Case 3, right hemihepatectomy was performed for HCC on a cirrhotic liver four weeks after right portal vein embolization, in which preoperative ICG R15 was 19.0%. Peak T. Bil level was 3.7 mg/100 ml with uneventful postoperative course. In Case 4 with a huge cholangioma, right trisegmentectomy was performed. Peak serum T. Bil level was 1.7 mg/100 ml in this uneventful postoperative course. In Case 3 and Case 4, portal blood flow, measured by Doppler ultrasonography, was markedly increased by PGE1 infusion. From these results, intra-arterial PGE1 infusion might be useful in prevention of postoperative liver failure after major hepatic resection.
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Affiliation(s)
- T Sato
- Department of Surgery, Akita University School of Medicine, Japan
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Hong JP, Chung YK, Chung SH. The effect of prostaglandin E1 versus ischemia-reperfusion injury of musculocutaneous flaps. Ann Plast Surg 2001; 47:316-21. [PMID: 11562038 DOI: 10.1097/00000637-200109000-00016] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The purpose of this study was twofold. To evaluate whether prostaglandin El can increase the survival of the flap, and to determine its function against ischemia-reperfusion injury in musculocutaneous flaps. Thirty-five Sprague-Dawley rats weighing 250 to 350 g were analyzed. The transverse rectus abdominis musculocutaneous flap was used in all rats. The rats were divided into three groups: group 1 (N = 15), the control group with 4-hour ischemic injury and intraflap injection of normal saline followed by reperfusion; group 2 (N = 15), prostaglandin E1 intraflap injection of 1 microg immediately after ischemic injury and reperfusion 4 hours later; and group 3 (N = 5), the sham-operated group. Analysis consisted of flap skin survival area measurements, immunohistochemical study using anti-intercellular adhesion molecule (anti-ICAM-1) monoclonal antibody, and histological evaluation including endothelium-sticking leukocytes at 24 hours and 5 days after reperfusion. The group treated with prostaglandin E1 showed immunohistochemical findings with decreased expression of ICAM-1 on the surface of the endothelium, and histology showed significant (p < 0.01) reduction of leukocyte adhesion at 24 hours and 5 days after reperfusion. These two factors were considered to play a role against ischemia-reperfusion injury, and led to improved survival of the flap. These results suggest that prostaglandin E1 may increase flap survival and may have a protective mechanism against ischemia-reperfusion injury by decreasing leukocyte-endothelial cell adhesion through decreased expression of ICAM-1.
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Affiliation(s)
- J P Hong
- Department of Plastic and Reconstructive Surgery, Yonsei University Wonju College of Medicine, Kangwondo, Korea
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Oe S, Hiros T, Fujii H, Yasuchika K, Nishio T, Iimuro Y, Morimoto T, Nagao M, Yamaoka Y. Continuous intravenous infusion of deleted form of hepatocyte growth factor attenuates hepatic ischemia-reperfusion injury in rats. J Hepatol 2001; 34:832-9. [PMID: 11451166 DOI: 10.1016/s0168-8278(01)00030-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND/AIMS Although beneficial roles of hepatocyte growth factor (HGF) and its variants on several hepatic disorders have been reported, their effects on hepatic ischemia-reperfusion (IR) injury remain undetermined. We investigated the action of a deleted form of HGF (dHGF) on hepatic IR injury in rats. METHODS dHGF or phosphate-buffered saline was continuously infused intravenously for 20 h prior to a 20-min occlusion of hepatic vessels. Samples were taken before and after IR, for measurement of serum dHGF and released enzymes, liver gamma-glutamylcysteinyl glycine (GSH) level, as well as histological and immunohistochemical examinations. RESULTS After reperfusion, histological injury, as well as increase in the serum activities of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and creatine kinase-BB were significantly attenuated in the dHGF-treated rats. dHGF maintained a high GSH level and suppressed oxidative stress and intercellular adhesion molecule-1 (ICAM-1) expression on sinusoidal endothelial cells (SECs), on which c-Met was not detected. IR caused activation of c-Met expression, which was milder in the dHGF-treated group, in hepatocytes at the pericentral region. CONCLUSIONS dHGF attenuated liver injury after IR. It also maintained a higher GSH level, depressed oxidative stress and inhibited ICAM-1 expression on c-Met negative SECs, suggesting a paracrine effect of dHGF.
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Affiliation(s)
- S Oe
- Department of Gastroenterological Surgery, Kyoto University Graduate School of Medicine, Japan.
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Lille ST, Lefler SR, Mowlavi A, Suchy H, Boyle EM, Farr AL, Su CY, Frank N, Mulligan DC. Inhibition of the initial wave of NF-kappaB activity in rat muscle reduces ischemia/reperfusion injury. Muscle Nerve 2001; 24:534-41. [PMID: 11268026 DOI: 10.1002/mus.1037] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Nuclear factor kappaB (NF-kappaB) is thought to play an important role in the expression of genes expressed in response to ischemia/reperfusion (I/R) injury. In this report, the activation of NF-kappaB in rat skeletal muscle during reperfusion following a 4-h ischemic period was studied. NF-kappaB activation displayed a biphasic pattern, showing peak activities from 30 min to 3 h postperfusion and 6 h to 16 h postperfusion, with a decline to baseline binding activity levels between 3 h and 6 h. Inhibition of NF-kappaB activation was investigated using proline dithiocarbamate (Pro-DTC). NF-kappaB binding activity during reperfusion was significantly reduced by intravenous administration of Pro-DTC. Additionally, Pro-DTC resulted in decreased muscle edema and neutrophil activity, with an increased percentage of muscle survival compared with vehicle controls. These results demonstrate that NF-kappaB is activated during reperfusion in a biphasic manner and that the regulation of the initial phase of NF-kappaB activation affords physiological protection against a severe ischemic stress. Selective inhibition of NF-kappaB during early reperfusion may therefore be a therapeutic intervention for I/R injury.
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Affiliation(s)
- S T Lille
- Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona 85287-1604, USA
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Kawamura T, Nara N, Kadosaki M, Inada K, Endo S. Prostaglandin E1 reduces myocardial reperfusion injury by inhibiting proinflammatory cytokines production during cardiac surgery. Crit Care Med 2000; 28:2201-8. [PMID: 10921541 DOI: 10.1097/00003246-200007000-00004] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE To determine the influence of prostaglandin E1 (PGE1) on the cytokine balance and myocardial protection during cardiac surgery. DESIGN Prospective, randomized, nonblinded study. SETTING University hospital. PATIENTS A total of 19 patients on cardiopulmonary bypass undergoing cardiac surgery. INTERVENTIONS According to randomized sequence, the patients received PGE1 (0.02 approximately 0.05 microg x kg(-1) x min(-1)) from the beginning of surgery to the end of study (PGE1 group, n = 11) or nothing (control group, n = 8). MEASUREMENTS AND MAIN RESULTS Interleukin (IL)-6, IL-8, IL-10, IL-1 receptor antagonist (IL-1ra), soluble tumor necrosis factor receptor I (sTNF RI), and soluble tumor necrosis factor receptor II (sTNF RII) were measured by enzyme-linked immunosorbent assays. Troponin-T and isoenzyme of creatine kinase with muscle and brain subunits (CK-MB) were measured by enzyme immunoassay and ultraviolet absorption spectrophotometry method, respectively. Serum IL-6 and IL-8 concentrations in both groups increased significantly from 60 mins after declamping the aorta compared with preoperative value (p < .001), However, the increases were greater in the control group than in the PGE1 group (p < .01). Serum IL-10, IL-1ra, sTNF RI, and sTNF RII concentrations increased significantly from 60 mins after declamping the aorta compared with preoperative values in two groups (p < .001, respectively). There were no differences between the two groups. Serum troponin T and CK-MB concentrations increased significantly in the two groups from 60 mins after declamping the aorta (p < .001), but these increases were greater in the control group than in the PGE1 group (p < .01). IL-6 and IL-8 levels correlated with CK-MB concentration (r2 = 0.49, r2 = 0.36; p > .001 respectively). CONCLUSIONS PGE1 suppressed the production of IL-6 and IL-8 but not IL-10, IL-1ra, sTNF RI, or sTNF RII. The change in the balance between pro-and anti-inflammatory cytokines may be one of the most important cytoprotective mechanisms of PGE1.
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Affiliation(s)
- T Kawamura
- Department of Anesthesiology, School of Medicine, Iwate Medical University, Morioka, Japan
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Ohmori M, Miyashita F, Uchida H, Kitoh Y, Tsuruoka S, Harada K, Sugimoto K, Fujimura A, Kobayashi E. Effect of erythromycin on ischemia-reperfusion injury of liver in rats. Transplant Proc 2000; 32:811-4. [PMID: 10856595 DOI: 10.1016/s0041-1345(00)00992-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- M Ohmori
- Department of Clinical Pharmacology, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan
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Hofbauer R, Moser D, Kaye AD, Knapp S, Gmeiner B, Kapiotis S, Wagner O, Frass M. Prostaglandin E(1) is able to increase migration of leukocytes through endothelial cell monolayers. Microvasc Res 2000; 59:354-60. [PMID: 10792966 DOI: 10.1006/mvre.1999.2220] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Leukocyte interactions with endothelial cells play an important role during inflammatory processes. Leukocytes pass a monolayer of endothelial cells (ECM) to migrate into the extravascular space. The aim of the current study was to investigate whether prostaglandin E(1) (PGE(1)) influences the process of leukocyte migration. In a prospective controlled study, the influence of prostaglandin E(1) (50-5000 ng/mL) on leukocyte migration through endothelial cell monolayers (n = 7) was investigated. Human umbilical endothelial cells (HUVEC) and/or leukocytes were preincubated with clinically relevant, higher, and lower concentrations of prostaglandin E(1) and the amount of leukocyte migration after 3 h was measured. HUVEC were cultured on microporous membrane filters until achievement of a monolayer for investigation of leukocyte migration. Polymorphonuclear leukocytes (PMNL) were isolated from healthy volunteers and PMNL migration was studied under the influence of PGE(1). In clinically relevant concentrations, PGE(1) was able to increase significantly leukocyte migration through endothelial cell monolayers (205 +/- 7.8%, P < 0.05 compared to control; when treating PMNL alone, migration rate was 120 +/- 9.2% compared to control, ns; only endothelial cell monolayers treated up to 145 +/- 10.2%, P < 0.05 compared to control) showing a dose-dependent effect. In this assay, both cell types (PMNL and ECM) could be treated simultaneously, simulating the clinical situation after an iv administration. In conclusion, PGE(1) is able to increase leukocyte migration through endothelial cell monolayers when both cell types are pretreated. The treatment of either leukocytes or endothelial cell monolayers in the cell coculture showed no significant increase. These findings support the theory that prostaglandins may play a major role during inflammation. Future clinical studies are warranted to confirm this hypothesis.
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Affiliation(s)
- R Hofbauer
- Department of Medical and Chemical Laboratory Diagnostics, University of Vienna, Vienna, Austria
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Farmer DG, Amersi F, Kupiec-Weglinski J, Busuttil RW. Current status of ischemia and reperfusion injury in the liver. Transplant Rev (Orlando) 2000. [DOI: 10.1053/tr.2000.4651] [Citation(s) in RCA: 92] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
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Tromp SC, Tangelder GJ, Slaaff DW, Reneman RS, van Velzen S, oude Egbrink MG. The influence of prostaglandins on leukocyte-endothelium interactions in rabbit mesenteric venules. Prostaglandins Other Lipid Mediat 2000; 60:71-82. [PMID: 10680777 DOI: 10.1016/s0090-6980(99)00051-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Contradictory results have been reported concerning the effects of prostaglandins (PGs) on leukocyte-endothelium interactions. Therefore, we investigated the in vivo effects of PGE1, PGE2, Iloprost (a stable PGI2-analogue), and also of a combination of these PGs on leukocyte rolling and FMLP-induced leukocyte adhesion in venules of rabbit mesentery. This preparation was used because of its low level of vasoactivity, eliminating hemodynamic effects on leukocyte-endothelium interactions. The mesentery was superfused with PGs or vehicle. After 30 min FMLP was added to the PG-solution for 15 min, whereupon the tissue was superfused with the PG-solution alone for another 30 min. Neither the PGs nor the cocktail influenced leukocyte rolling. During FMLP administration leukocyte adhesion increased and leukocyte rolling decreased; adhesion was highest in the presence of PGE2. The FMLP-induced decrease in leukocyte rolling was similar in all groups. After FMLP administration had been stopped the number of adherent cells almost returned to baseline and the level of leukocyte rolling increased, the baseline level being reached only in the presence of PGE2. In conclusion, these findings indicate that the effects of PGs on leukocyte-endothelium interactions are limited.
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Affiliation(s)
- S C Tromp
- Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands
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Abstract
Facilitation of solid organ and cell transplantation depends on metabolic and immunologic factors that can be manipulated ex vivo and in vivo using gene transfer technology. Vectors have been developed which can optimally transfer relevant genes to various tissues and organs. Interventions aimed at promoting tissue preservation before transplantation, prevention of oxidative stress and immunological rejection have recently become attractive options using viral and nonviral gene delivery vehicles. Further understanding of the mechanisms involved in tolerance induction as well as the facilitation of xenogeneic engraftment have made possible a variety of avenues that can be exploited using gene transfer technology.
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Affiliation(s)
- N Giannoukakis
- Department of Molecular Genetics and Biochemistry, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15261, USA
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