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Casillas-Ramírez A, Micó-Carnero M, Sánchez-González A, Maroto-Serrat C, Trostchansky A, Peralta C. NO-IL-6/10-IL-1β axis: a new pathway in steatotic and non-steatotic liver grafts from brain-dead donor rats. Front Immunol 2023; 14:1178909. [PMID: 37593740 PMCID: PMC10427871 DOI: 10.3389/fimmu.2023.1178909] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 07/11/2023] [Indexed: 08/19/2023] Open
Abstract
INTRODUCTION Brain death (BD) and steatosis are both risk factors for organ dysfunction or failure in liver transplantation (LT). MATERIAL AND METHODS Here, we examine the role of interleukin 6 (IL- 6) and IL-10 in LT of both non-steatotic and steatotic liver recovered from donors after brain death (DBDs), as well as the molecular signaling pathways underlying the effects of such cytokines. RESULTS BD reduced IL-6 levels only in nonsteatotic grafts, and diminished IL-10 levels only in steatotic ones. In both graft types, BD increased IL-1β, which was associated with hepatic inflammation and damage. IL-6 administration reduced IL-1β only in non-steatotic grafts and protected them against damage and inflammation. Concordantly, IL-1β inhibition via treatment with an IL-1 receptor antagonist caused the same benefits in non-steatotic grafts. Treatment with IL-10 decreased IL-1β only in steatotic grafts and reduced injury and inflammation specifically in this graft type. Blockading the IL-1β effects also reduced damage and inflammation in steatotic grafts. Also, blockade of IL-1β action diminished hepatic cAMP in both types of livers, and this was associated with a reduction in liver injury and inflammation, then pointing to IL-1β regulating cAMP generation under LT and BD conditions. Additionally, the involvement of nitric oxide (NO) in the effects of interleukins was evaluated. Pharmacological inhibition of NO in LT from DBDs prompted even more evident reductions of IL-6 or IL-10 in non-steatotic and steatotic grafts, respectively. This exacerbated the already high levels of IL-1β seen in LT from DBDs, causing worse damage and inflammation in both graft types. The administration of NO donors to non-steatotic grafts potentiated the beneficial effects of endogenous NO, since it increased IL-6 levels, and reduced IL-1β, inflammation, and damage. However, treatment with NO donors in steatotic grafts did not modify IL-10 or IL-1β levels, but induced more injurious effects tan the induction of BD alone, characterized by increased nitrotyrosine, lipid peroxidation, inflammation, and hepatic damage. CONCLUSION Our study thus highlights the specificity of new signaling pathways in LT from DBDs: NO-IL-6-IL-1β in non-steatotic livers and NO-IL-10-IL-1β in steatotic ones. This opens up new therapeutic targets that could be useful in clinical LT.
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Affiliation(s)
- Araní Casillas-Ramírez
- Department of Teaching and Research Sub-Direction, Hospital Regional de Alta Especialidad de Ciudad Victoria “Bicentenario 2010”, Ciudad Victoria, Mexico
- Facultad de Medicina e Ingeniería en Sistemas Computacionales de Matamoros, Universidad Autónoma de Tamaulipas, Matamoros, Mexico
| | - Marc Micó-Carnero
- Department of Liver, Digestive System and Metabolism, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
| | - Alfredo Sánchez-González
- Department of Teaching and Research Sub-Direction, Hospital Regional de Alta Especialidad de Ciudad Victoria “Bicentenario 2010”, Ciudad Victoria, Mexico
| | - Cristina Maroto-Serrat
- Department of Liver, Digestive System and Metabolism, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
| | - Andrés Trostchansky
- Departamento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
| | - Carmen Peralta
- Department of Liver, Digestive System and Metabolism, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
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Yan X, Huang S, Li F, Jiang L, Jiang Y, Liu J. Short-term outcomes of perioperative glucocorticoid administration in patients undergoing liver surgery: a systematic review and meta-analysis of randomised controlled trials. BMJ Open 2023; 13:e068969. [PMID: 37169506 DOI: 10.1136/bmjopen-2022-068969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/13/2023] Open
Abstract
OBJECTIVE The purpose of this systematic review and meta-analysis was to investigate whether glucocorticoid might be beneficial after hepatectomy. DESIGN Systematic review and meta-analysis. DATA SOURCES PubMed, Embase, Cochrane Library and Web of Science. ELIGIBILITY CRITERIA We included studies assessing the efficacy of perioperative glucocorticoid administration in patients undergoing liver surgery. DATA EXTRACTION AND SYNTHESIS Four data bases were retrieved for all randomised controlled trials. We considered postoperative complications, hospital stay and postoperative chemistry evaluations as outcomes. Pooled effects of dichotomic variables were expressed as relative risk (RR) with a 95% CI. The mean difference was used for continuous variables and an inverse variance statistical method was adopted. RESULTS Fourteen studies with 1205 patients were included. Lower risk of overall complications was associated with glucocorticoid (RR, 0.77; 95% CI 0.64 to 0.92), while no difference was found in hospital stay (RR, 0.02; 95% CI -0.47 to 0.51). There were also improvements in postoperative chemistry evaluations including interleukin 6 on day 1 and 3, C reactive protein on day 1, 2 and 3, international normalised ratio on day 2, total bilirubin on day 1, 2, 3 and 5, albumin on day 1. CONCLUSION Current evidence indicated that perioperative glucocorticoid administration for patients undergoing hepatectomy reduced the risk of overall complications with inhibited postoperative inflammatory response and improved postoperative liver function. PROSPERO REGISTRATION NUMBER CRD42022307533.
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Affiliation(s)
- Xiangyu Yan
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Songhan Huang
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Feiyu Li
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Liyong Jiang
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yong Jiang
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jun Liu
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital affliated to Shandong First Medical University, Jinan, China
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Shibata K, Hayasaka T, Sakamoto S, Hashimoto S, Kawamura N, Fujiyoshi M, Kimura T, Shimamura T, Fukai M, Taketomi A. Warm Ischemia Induces Spatiotemporal Changes in Lysophosphatidylinositol That Affect Post-Reperfusion Injury in Normal and Steatotic Rat Livers. J Clin Med 2023; 12:jcm12093163. [PMID: 37176603 PMCID: PMC10179083 DOI: 10.3390/jcm12093163] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 04/24/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
Warm ischemia-reperfusion injury is a prognostic factor for hepatectomy and liver transplantation. However, its underlying molecular mechanisms are unknown. This study aimed to elucidate these mechanisms and identify the predictive markers of post-reperfusion injury. Rats with normal livers were subjected to 70% hepatic warm ischemia for 15, 30, or 90 min, while those with steatotic livers were subjected to 70% hepatic warm ischemia for only 30 min. The liver and blood were sampled at the end of ischemia and 1, 6, and 24 h after reperfusion. The serum alanine aminotransferase (ALT) activity, Suzuki injury scores, and lipid peroxidation (LPO) products were evaluated. The ALT activity and Suzuki scores increased with ischemic duration and peaked at 1 and 6 h after reperfusion, respectively. Steatotic livers subjected to 30 min ischemia and normal livers subjected to 90 min ischemia showed comparable injury. A similar trend was observed for LPO products. Imaging mass spectrometry of normal livers revealed an increase in lysophosphatidylinositol (LPI (18:0)) and a concomitant decrease in phosphatidylinositol (PI (18:0/20:4)) in Zone 1 (central venous region) with increasing ischemic duration; they returned to their basal values after reperfusion. Similar changes were observed in steatotic livers. Hepatic warm ischemia time-dependent acceleration of PI (18:0/20:4) to LPI (18:0) conversion occurs initially in Zone 1 and is more pronounced in fatty livers. Thus, the LPI (18:0)/PI (18:0/20:4) ratio is a potential predictor of post-reperfusion injury.
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Affiliation(s)
- Kengo Shibata
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Takahiro Hayasaka
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Sodai Sakamoto
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Satsuki Hashimoto
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Norio Kawamura
- Department of Transplant Surgery, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Masato Fujiyoshi
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Taichi Kimura
- Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Tsuyoshi Shimamura
- Division of Organ Transplantation, Hokkaido University Hospital, Sapporo 060-8648, Japan
| | - Moto Fukai
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
- Department of Transplant Surgery, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
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Xu Y, Wang Y, Ji X. Immune and inflammatory mechanism of remote ischemic conditioning: A narrative review. Brain Circ 2023; 9:77-87. [PMID: 37576576 PMCID: PMC10419737 DOI: 10.4103/bc.bc_57_22] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 02/06/2023] [Accepted: 02/17/2023] [Indexed: 08/15/2023] Open
Abstract
The benefits of remote ischemic conditioning (RIC) on multiple organs have been extensively investigated. According to existing research, suppressing the immune inflammatory response is an essential mechanism of RIC. Based on the extensive effects of RIC on cardiovascular and cerebrovascular diseases, this article reviews the immune and inflammatory mechanisms of RIC and summarizes the effects of RIC on immunity and inflammation from three perspectives: (1) the mechanisms of the impact of RIC on inflammation and immunity; (2) evidence of the effects of RIC on immune and inflammatory processes in ischaemic stroke; and (3) possible future applications of this effect, especially in systemic infectious diseases such as sepsis and sepsis-associated encephalopathy. This review explores the possibility of using RIC as a treatment in more inflammation-related diseases, which will provide new ideas for the treatment of this kind of disease.
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Affiliation(s)
- Yi Xu
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
- China-America Institute of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Yuan Wang
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Xunming Ji
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
- China-America Institute of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
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Ma Y, Wang C, Xu G, Yu X, Fang Z, Wang J, Li M, Kulaixi X, Ye J. Transcriptional changes in orthotopic liver transplantation and ischemia/reperfusion injury. Transpl Immunol 2022; 74:101638. [PMID: 35667543 DOI: 10.1016/j.trim.2022.101638] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 05/29/2022] [Accepted: 05/31/2022] [Indexed: 02/07/2023]
Abstract
Background There are few effective targeting strategies to reduce liver ischemia-reperfusion injury (IRI), which is one of the reasons for the poor prognosis of liver transplant recipients. Methods A systematic approach combining gene expression with protein interaction (PPI) network was used to screen the characteristic genes and related biological functions of post-transplant. Differentially expressed genes (DEGs) between IRI+ and IRI- were identified. Logistic regression model and receiver operating characteristic (ROC) curve were used to identify potential target genes of IRI. The expression of key genes was verified by qRT-PCR and Western-blot experiments. Finally, the ssGSEA was used to identify the immune cell infiltration in patients with IRI. Results The 283 common DEGs in GSE87487 and GSE151648 were mainly related to apoptosis and IL-17 signaling pathway. Through PPI network and logistic regression analysis, we identified that IL6, CCL2 and CXCL8 may be involved in the ischemia/reperfusion (IR) process. In addition, 32 genes were showed associated with IRI through inflammatory and metabolic pathways. Among the key genes identified, the differential expression of AGBL4, CILP2 and IL4I1 was verified by molecular experiments. Th17 cells of differentially infiltrated immune cells were positively correlated with CILP2 and IL4I1. The difference of Th17 cells between IRI+ and IRI- was verified by flow cytometry. Conclusion The study showed that AGBL4, CILP2 and IL4I1 were associated with IRI. Th17 cells may be associated with the regulation of IRI by key genes. These genes and related pathways may be targets for improving IRI.
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Affiliation(s)
- Yan Ma
- Department of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, Xinyi, road, Xinshi district, Urumqi, 830054, China
| | - Chunsheng Wang
- Department of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, Xinyi, road, Xinshi district, Urumqi, 830054, China.; Department of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, Xinyi, road, Xinshi district, Urumqi, 830054, China
| | - Guiping Xu
- Department of Anesthesiology, People's Hospital of Xinjiang Uygur Autonomous Region, Tianchi Road, Tianshan District, Urumqi 830000, China
| | - Xiaodong Yu
- Department of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, Xinyi, road, Xinshi district, Urumqi, 830054, China
| | - Zhiyuan Fang
- Xinjiang Medical University, Xinshi District, Urumqi, 830011, China
| | - Jialing Wang
- Xinjiang Medical University, Xinshi District, Urumqi, 830011, China
| | - Meng Li
- Xinjiang Medical University, Xinshi District, Urumqi, 830011, China
| | | | - Jianrong Ye
- Department of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, Xinyi, road, Xinshi district, Urumqi, 830054, China..
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Nakata Y, Kono H, Akazawa Y, Hirayama K, Wakana H, Fukushima H, Sun C, Fujii H. Role of podoplanin and Kupffer cells in liver injury after ischemia-reperfusion in mice. Surg Today 2022; 52:344-353. [PMID: 34568969 DOI: 10.1007/s00595-021-02378-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 05/21/2021] [Indexed: 02/02/2023]
Abstract
AIM To investigate the relationship between the intrahepatic expression of podoplanin (PDPN) and Kupffer cells (KCs) in ischemia-reperfusion (I/R) liver damage. METHODS C57Bl/6 mice were injected with 200 µl of clodronate liposomes (macrophage depletion; MDP group) to deplete KCs or control liposomes (control group) via the ophthalmic vein plexus 24 h prior to ischemia. Animals were subjected to 90 min of partial hepatic ischemia (70%), followed by reperfusion, and were then killed at designated time points. Serum and liver tissues were harvested for further analyses. RESULTS Serum ALT levels, mortality rates, and the percentage of necrotic area in liver sections were significantly higher in the MDP group than in the control group. PDPN was expressed in the lymphatic epithelium, interlobular bile duct epithelium, and in some hepatocytes in each group. Its expression in hepatocytes was down-regulated in the MDP group. The accumulation of platelets in the sinusoid was reduced 6 h after I/R in the MDP group. Tissue HGF and IGF-1 levels decreased in the MDP group. CONCLUSIONS These results suggest that KCs play a key role in the activation of platelets through direct contact with PDPN-positive hepatocytes in I/R livers.
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Affiliation(s)
- Yuuki Nakata
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan
| | - Hiroshi Kono
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan.
| | - Yoshihiro Akazawa
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan
| | - Kazuyoshi Hirayama
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan
| | - Hiroyuki Wakana
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan
| | - Hisataka Fukushima
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan
| | - Chao Sun
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan
- Department of Orthopedic Surgery, The Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010030, China
| | - Hideki Fujii
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan
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Tao L, Pang Y, Wang A, Li L, Shen Y, Xu X, Li J. Functional miR-142a-3p Induces Apoptosis and Macrophage Polarization by Targeting tnfaip2 and glut3 in Grass Carp ( Ctenopharyngodon idella). Front Immunol 2021; 12:633324. [PMID: 34262558 PMCID: PMC8273434 DOI: 10.3389/fimmu.2021.633324] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 06/08/2021] [Indexed: 11/13/2022] Open
Abstract
In the process of microbial invasion, the inflammation reaction is induced to eliminate the pathogen. However, un-controlled or un-resolved inflammation can lead to tissue damage and death of the host. MicroRNAs (miRNAs) are the signaling regulators that prevent the uncontrolled progress of an inflammatory response. Our previous work strongly indicated that miR-142a-3p is related to the immune regulation in grass carp. In the present study, we found that the expression of miR-142a-3p was down-regulated after infection by Aeromonas hydrophila. tnfaip2 and glut3 were confirmed as be the target genes of miR-142a-3p, which were confirmed by expression correlation analysis, gene overexpression, and dual luciferase reporter assay. The miR-142a-3p can reduce cell viability and stimulate cell apoptosis by targeting tnfaip2 and glut3. In addition, miR-142a-3p also regulates macrophage polarization induced by A. hydrophila. Our results suggest that miR-142a-3p has multiple functions in host antibacterial immune response. Our research provides further understanding of the molecular mechanisms between miRNAs and their target genes, and provides a new insights for the development of pro-resolution strategies for the treatment of complex inflammatory diseases in fish.
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Affiliation(s)
- Lizhu Tao
- Key Laboratory of Freshwater Aquatic Genetic Resources Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai, China.,Institute of Fisheries of Chengdu Agriculture and Forestry Academy, Chengdu, China
| | - Yifan Pang
- National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai, China
| | - Anqi Wang
- Shanghai Engineering Research Center of Aquaculture, Shanghai Ocean University, Shanghai, China
| | - Lisen Li
- Comparative Endocrinology and Integrative Biology, Centre of Marine Sciences, Universidade Do Algarve, Faro, Portugal
| | - Yubang Shen
- National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai, China
| | - Xiaoyan Xu
- Key Laboratory of Freshwater Aquatic Genetic Resources Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai, China.,Shanghai Engineering Research Center of Aquaculture, Shanghai Ocean University, Shanghai, China
| | - Jiale Li
- Key Laboratory of Freshwater Aquatic Genetic Resources Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai, China.,National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai, China.,Shanghai Engineering Research Center of Aquaculture, Shanghai Ocean University, Shanghai, China
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Neri AA, Dontas IA, Iliopoulos DC, Karatzas T. Pathophysiological Changes During Ischemia-reperfusion Injury in Rodent Hepatic Steatosis. In Vivo 2021; 34:953-964. [PMID: 32354880 DOI: 10.21873/invivo.11863] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 02/03/2020] [Accepted: 02/07/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND/AIM Ischemia and reperfusion injuries may produce deleterious effects on hepatic tissue after liver surgery and transplantation. The impact of ischemia-reperfusion injury (IRI) on the liver depends on its substrate, the percentage of liver ischemic tissue subjected to IRI and the ischemia time. The consequences of IRI are more evident in pathologic liver substrates, such as steatotic livers. This review is the result of an extended bibliographic PubMed search focused on the last 20 years. It highlights basic differences encountered during IRI in lean and steatotic livers based on studies using rodent experimental models. CONCLUSION The main difference in cell death between lean and steatotic livers is the prevalence of apoptosis in the former and necrosis in the latter. There are also major changes in the effect of intracellular mediators, such as TNFα and IL-1β. Further experimental studies are needed in order to increase current knowledge of IRI effects and relevant mechanisms in both lean and steatotic livers, so that new preventive and therapeutic strategies maybe developed.
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Affiliation(s)
- Anna-Aikaterini Neri
- Laboratory for Research of the Musculoskeletal System "Th. Garofalidis", KAT Hospital, School of Medicine, National & Kapodistrian University of Athens, Kifissia, Greece
| | - Ismene A Dontas
- Laboratory for Research of the Musculoskeletal System "Th. Garofalidis", KAT Hospital, School of Medicine, National & Kapodistrian University of Athens, Kifissia, Greece
| | - Dimitrios C Iliopoulos
- Laboratory of Experimental Surgery & Surgical Research "N.S. Christeas", School of Medicine, National & Kapodistrian University of Athens, Athens, Greece
| | - Theodore Karatzas
- Laboratory of Experimental Surgery & Surgical Research "N.S. Christeas", School of Medicine, National & Kapodistrian University of Athens, Athens, Greece.,2 Department of Propedeutic Surgery, School of Medicine, National & Kapodistrian University of Athens, Athens, Greece
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Baidya R, Crawford DHG, Gautheron J, Wang H, Bridle KR. Necroptosis in Hepatosteatotic Ischaemia-Reperfusion Injury. Int J Mol Sci 2020; 21:ijms21165931. [PMID: 32824744 PMCID: PMC7460692 DOI: 10.3390/ijms21165931] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 08/12/2020] [Accepted: 08/12/2020] [Indexed: 02/07/2023] Open
Abstract
While liver transplantation remains the sole treatment option for patients with end-stage liver disease, there are numerous limitations to liver transplantation including the scarcity of donor livers and a rise in livers that are unsuitable to transplant such as those with excess steatosis. Fatty livers are susceptible to ischaemia-reperfusion (IR) injury during transplantation and IR injury results in primary graft non-function, graft failure and mortality. Recent studies have described new cell death pathways which differ from the traditional apoptotic pathway. Necroptosis, a regulated form of cell death, has been associated with hepatic IR injury. Receptor-interacting protein kinase 3 (RIPK3) and mixed-lineage kinase domain-like pseudokinase (MLKL) are thought to be instrumental in the execution of necroptosis. The study of hepatic necroptosis and potential therapeutic approaches to attenuate IR injury will be a key factor in improving our knowledge regarding liver transplantation with fatty donor livers. In this review, we focus on the effect of hepatic steatosis during liver transplantation as well as molecular mechanisms of necroptosis and its involvement during liver IR injury. We also discuss the immune responses triggered during necroptosis and examine the utility of necroptosis inhibitors as potential therapeutic approaches to alleviate IR injury.
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Affiliation(s)
- Raji Baidya
- Faculty of Medicine, The University of Queensland, Brisbane, Queensland QLD 4006, Australia; (R.B.); (D.H.G.C.)
- Gallipoli Medical Research Institute, Brisbane, Queensland QLD 4120, Australia;
| | - Darrell H. G. Crawford
- Faculty of Medicine, The University of Queensland, Brisbane, Queensland QLD 4006, Australia; (R.B.); (D.H.G.C.)
- Gallipoli Medical Research Institute, Brisbane, Queensland QLD 4120, Australia;
| | - Jérémie Gautheron
- Sorbonne University, Inserm, Centre de Recherche Saint-Antoine (CRSA), 75012 Paris, France;
- Institute of Cardiometabolism and Nutrition (ICAN), 75013 Paris, France
| | - Haolu Wang
- Gallipoli Medical Research Institute, Brisbane, Queensland QLD 4120, Australia;
- Diamantina Institute, The University of Queensland, Brisbane, Queensland QLD 4102, Australia
| | - Kim R. Bridle
- Faculty of Medicine, The University of Queensland, Brisbane, Queensland QLD 4006, Australia; (R.B.); (D.H.G.C.)
- Gallipoli Medical Research Institute, Brisbane, Queensland QLD 4120, Australia;
- Correspondence: ; Tel.: +61-7-3346-0698
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10
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Ye L, He S, Mao X, Zhang Y, Cai Y, Li S. Effect of Hepatic Macrophage Polarization and Apoptosis on Liver Ischemia and Reperfusion Injury During Liver Transplantation. Front Immunol 2020; 11:1193. [PMID: 32676077 PMCID: PMC7333353 DOI: 10.3389/fimmu.2020.01193] [Citation(s) in RCA: 107] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Accepted: 05/13/2020] [Indexed: 12/21/2022] Open
Abstract
Ischemia-reperfusion (I/R) injury is injury caused by a limited blood supply and subsequent blood supply recovery during liver transplantation. Serious ischemia-reperfusion injury is the main cause of transplant failure. Hepatic I/R is characterized by tissue hypoxia due to a limited blood supply and reperfusion inducing oxidative stress and an immune response. Studies have confirmed that Kupffer cells (KCs), resident macrophages in the liver, play a key role in aseptic inflammation induced by I/R. In liver macrophage polarization, M1 macrophages activated by interferon-γ (IFN-γ) and lipopolysaccharide (LPS) exert a pro-inflammatory effect and release a variety of inflammatory cytokines. M2 macrophages activated by IL-4 have an anti-inflammatory response. M1-type KCs are the dominant players in I/R as they secrete various pro-inflammatory cytokines that exacerbate the injury and recruit other types of immune cells via the circulation. In contrast, M2-type KCs can ameliorate I/R through unregulated anti-inflammatory factors. A new notion has been proposed that KC apoptosis may influence I/R in yet another manner as well. Management of KCs is expected to help improve I/R. This review summarizes the effects of hepatic macrophage polarization and apoptosis on liver I/R.
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Affiliation(s)
- Liping Ye
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Saiqin He
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
- Endoscopy Center, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Xinli Mao
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Yu Zhang
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Yue Cai
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Shaowei Li
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
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11
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Grezzana Filho TDJM, Longo L, Santos JLD, Gabiatti G, Boffil C, Santos EBD, Cerski CTS, Chedid MF, Corso CO. Induction of selective liver hypothermia prevents significant ischemia/reperfusion injury in Wistar rats after 24 hours. Acta Cir Bras 2020; 35:e202000205. [PMID: 32428061 PMCID: PMC7217597 DOI: 10.1590/s0102-865020200020000005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 12/14/2019] [Accepted: 01/19/2020] [Indexed: 02/08/2023] Open
Abstract
Purpose To investigate the effects of induction of selective liver hypothermia in a rodent model. Methods Seven male Wistar rats were subjected to 90 minutes of partial 70% liver ischemia and topic liver 26°C hypothermia (H group). Other seven male Wistar rats were subjected to 90 minutes of partial 70% normothermic liver ischemia (N group). Five additional rats underwent a midline incision and section of liver ligaments under normothermic conditions and without any liver ischemia (sham group). All animals were sacrificed 24-h after reperfusion, and livers were sampled for analyses. Pathology sections were scored for sinusoidal congestion, ballooning, hepatocelllular necrosis and the presence of neutrophilic infiltrates. Results At the end of the experiment, liver tissue expressions of TNF-ɑ, IL-1β, iNOS and TNF-ɑ/IL-10 ratio were significantly reduced in the H group compared to N group, whereas IL-10 and eNOS were significantly increased in H group. Histopathological injury scores revealed a significant decrease in ischemia/reperfusion (I/R) injuries in H group. Conclusion Selective liver hypothermia prevented I/R injury by inhibiting the release of inflammatory cytokines, preserves microcirculation, prevents hepatocellular necrosis and leukocyte infiltration, allowing maintenance of the liver architecture.
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Affiliation(s)
| | - Larisse Longo
- Liver Research Laboratory, HCPA, UFRGS, Porto Alegre, RS, Brazil
| | | | | | - Carlos Boffil
- Liver Research Laboratory, HCPA, UFRGS, Porto Alegre, RS, Brazil
| | | | | | - Marcio Fernandes Chedid
- Postgraduate Program in Surgical Sciences and Attending Liver Transplant Surgeon, HCPA, UFRGS, Porto Alegre, RS, Brazil
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12
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Sun H, McKeen T, Wang H, Ni HM. Necroptosis in ischemia-reperfusion injury of lean and steatotic livers. LIVER RESEARCH 2019. [DOI: 10.1016/j.livres.2019.09.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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13
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Álvarez-Mercado AI, Gulfo J, Romero Gómez M, Jiménez-Castro MB, Gracia-Sancho J, Peralta C. Use of Steatotic Grafts in Liver Transplantation: Current Status. Liver Transpl 2019; 25:771-786. [PMID: 30740859 DOI: 10.1002/lt.25430] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 02/02/2019] [Indexed: 12/12/2022]
Abstract
In the field of liver transplantation, the demand for adequate allografts greatly exceeds the supply. Therefore, expanding the donor pool to match the growing demand is mandatory. The present review summarizes current knowledge of the pathophysiology of ischemia/reperfusion injury in steatotic grafts, together with recent pharmacological approaches aimed at maximizing the utilization of these livers for transplantation. We also describe the preclinical models currently available to understand the molecular mechanisms controlling graft viability in this specific type of donor, critically discussing the heterogeneity in animal models, surgical methodology, and therapeutic interventions. This lack of common approaches and interventions makes it difficult to establish the pathways involved and the relevance of isolated discoveries, as well as their transferability to clinical practice. Finally, we discuss how new therapeutic strategies developed from experimental studies are promising but that further studies are warranted to translate them to the bedside.
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Affiliation(s)
- Ana I Álvarez-Mercado
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - José Gulfo
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Manuel Romero Gómez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas (CIBEREHD), Madrid, Spain
- Inter-Centre Unit of Digestive Diseases, Virgen del Rocio University Hospitals, Sevilla, Spain; Institute of Biomedicine of Seville, Seville, Spain
- Institute of Biomedicine of Seville, Seville, Spain
| | | | - Jordi Gracia-Sancho
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas (CIBEREHD), Madrid, Spain
- Hepatology, Department of Biomedical Research, University of Bern, Bern, Switzerland
| | - Carmen Peralta
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas (CIBEREHD), Madrid, Spain
- Universidad Internacional de Cataluña, Barcelona, Spain
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14
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Ni HM, Chao X, Kaseff J, Deng F, Wang S, Shi YH, Li T, Ding WX, Jaeschke H. Receptor-Interacting Serine/Threonine-Protein Kinase 3 (RIPK3)-Mixed Lineage Kinase Domain-Like Protein (MLKL)-Mediated Necroptosis Contributes to Ischemia-Reperfusion Injury of Steatotic Livers. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:1363-1374. [PMID: 31026418 DOI: 10.1016/j.ajpath.2019.03.010] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 02/12/2019] [Accepted: 03/21/2019] [Indexed: 02/07/2023]
Abstract
Increased hepatic ischemia-reperfusion (IR) injury in steatotic livers is a major reason for rejecting the use of fatty livers for liver transplantation. Necroptosis is implicated in the pathogenesis of fatty liver diseases. Necroptosis is regulated by three key proteins: receptor-interacting serine/threonine-protein kinase (RIPK)-1, RIPK3, and mixed-lineage kinase domain-like protein (MLKL). Here, we found that marked steatosis of the liver was induced when a Western diet was given in mice; steatosis was associated with the inhibition of hepatic proteasome activities and with increased levels of key necroptosis-related proteins. Mice fed a Western diet had more severe liver injury, as demonstrated by increases in serum alanine aminotransferase and necrotic areas of liver, after IR than did mice fed a control diet. Although hepatic steatosis was not different between Mlkl knockout mice and wild-type mice, Mlkl knockout mice had decreased hepatic neutrophil infiltration and inflammation and were protected from hepatic IR injury, irrespective of diet. Intriguingly, Ripk3 knockout or Ripk3 kinase-dead knock-in mice were protected against IR injury at the late phase but not the early phase, irrespective of diet. Overall, our findings indicate that liver steatosis exacerbates hepatic IR injury via increased MLKL-mediated necroptosis. Targeting MLKL-mediated necroptosis may help to improve outcomes in steatotic liver transplantation.
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Affiliation(s)
- Hong-Min Ni
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
| | - Xiaojuan Chao
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Joshua Kaseff
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Fengyan Deng
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Shaogui Wang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Ying-Hong Shi
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Tiangang Li
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
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15
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Yang F, Wang S, Liu Y, Zhou Y, Shang L, Feng M, Yuan X, Zhu W, Shi X. IRE1α aggravates ischemia reperfusion injury of fatty liver by regulating phenotypic transformation of kupffer cells. Free Radic Biol Med 2018; 124:395-407. [PMID: 29969718 DOI: 10.1016/j.freeradbiomed.2018.06.043] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 06/29/2018] [Accepted: 06/30/2018] [Indexed: 12/18/2022]
Abstract
Fatty liver is one of the widely accepted marginal donor for liver transplantation, but is also more sensitive to ischemia and reperfusion injury (IRI) and produces more reactive oxygen species (ROS). Moreover, so far, no effective method has been developed to alleviate it. Endoplasmic reticulum stress (ER-stress) of hepatocyte is associated with the occurrence of fatty liver disease, but ER-stress of kupffer cells (KCs) in fatty liver is not clear at all. This study evaluates whether ER-stress of KCs is activated in fatty liver and accelerate IRI of fatty livers. ER-stress of KCs was activated in fatty liver, especially the IRE1α signal pathway. KCs with activated ER-stress secreted more proinflammatory cytokine to induce its M1-phenotypic shift in fatty liver, resulting in more severe IRI. Also, activated ER-stress of BMDMs in vitro by tunicamycin can induce its pro-inflammatory shift and can be reduced by 4-PBA, an ER-stress inhibitor. Knockdown of IRE1α could regulate the STAT1 and STAT6 pathway of macrophage to inhibit the M1-type polarization and promote M2-phenotypic shift. Furthermore, transfusion of IRE1α-knockdown KCs significantly reduced the liver IRI as well as the ROS of HFD feeding mice. Altogether, these data demonstrated that IRE1α of KCs may be a potential target to reduce the fatty liver associated IRI in liver transplantation.
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Affiliation(s)
- Faji Yang
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China
| | - Shuai Wang
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China
| | - Yang Liu
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China
| | - Yuan Zhou
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China
| | - Longcheng Shang
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China
| | - Min Feng
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China
| | - Xianwen Yuan
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China
| | - Wei Zhu
- Department of Anesthesiology, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China.
| | - Xiaolei Shi
- Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China.
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16
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Lu TF, Yang TH, Zhong CP, Shen C, Lin WW, Gu GX, Xia Q, Xu N. Dual Effect of Hepatic Macrophages on Liver Ischemia and Reperfusion Injury during Liver Transplantation. Immune Netw 2018; 18:e24. [PMID: 29984042 PMCID: PMC6026692 DOI: 10.4110/in.2018.18.e24] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 06/20/2018] [Accepted: 06/21/2018] [Indexed: 12/14/2022] Open
Abstract
Ischemia-reperfusion injury (IRI) is a major complication in liver transplantation (LT) and it is closely related to the recovery of grafts' function. Researches has verified that both innate and adaptive immune system are involved in the development of IRI and Kupffer cell (KC), the resident macrophages in the liver, play a pivotal role both in triggering and sustaining the sterile inflammation. Damage-associated molecular patterns (DAMPs), released by the initial dead cell because of the ischemia insult, firstly activate the KC through pattern recognition receptors (PRRs) such as toll-like receptors. Activated KCs is the dominant players in the IRI as it can secret various pro-inflammatory cytokines to exacerbate the injury and recruit other types of immune cells from the circulation. On the other hand, KCs can also serve in a contrary way to ameliorate IRI by upregulating the anti-inflammatory factors. Moreover, new standpoint has been put forward that KCs and macrophages from the circulation may function in different way to influence the inflammation. Managements towards KCs are expected to be the effective way to improve the IRI.
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Affiliation(s)
- Tian-Fei Lu
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Tai-Hua Yang
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medicine School, Hannover 30625, Germany
| | - Cheng-Peng Zhong
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Chuan Shen
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Wei-Wei Lin
- Department of Laboratory, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Guang-Xiang Gu
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Ning Xu
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
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17
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Czigany Z, Bleilevens C, Beckers C, Stoppe C, Möhring M, Fülöp A, Szijarto A, Lurje G, Neumann UP, Tolba RH. Limb remote ischemic conditioning of the recipient protects the liver in a rat model of arterialized orthotopic liver transplantation. PLoS One 2018; 13:e0195507. [PMID: 29617450 PMCID: PMC5884561 DOI: 10.1371/journal.pone.0195507] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2017] [Accepted: 02/24/2018] [Indexed: 02/06/2023] Open
Abstract
Background Ischemic-reperfusion (IR) injury still represents a major concern in clinical transplantation, especially in the era of extreme organ shortage and extended criteria donor organs. In the present study we aimed to investigate the hepatoprotective effects of remote ischemic conditioning (RIC) in a rat model of arterialized orthotopic liver transplantation (OLT). Methods Male Lewis rats were used (n = 144 / 72 OLT cases; 240–340g) as donors and recipients. Livers were flushed and stored in 4°C HTK-solution for 8h before implantation. Recipients were randomly allocated into three experimental groups: RIC 1, RIC 2, Control. In RIC 1, RIC 2 groups, RIC was applied in the recipient before hepatectomy or after reperfusion (4x5-5min IR via clamping the infrarenal aorta), respectively. Animals were sacrificed at 1, 3, 24, 168h post-reperfusion (n = 6 recipient/group/time point). Hepatocellular injury, graft circulation, serum cytokines, tissue redox-stress and adenosine-triphosphate (ATP) levels have been assessed. Additional markers were analyzed, using Western blotting and reverse-transcription polymerase chain reaction. Results RIC 1 group showed significantly (p<0.05) improved portal venous and microcirculation flow as well as velocity. RIC has significantly reduced tissue injury according to the serum levels of transaminases and results of histopathological evaluation. Reduced TUNEL-staining (p<0.01 RIC 1–2 vs. Control) and elevated pBAD/BAD ratio was detected in the RIC groups (p<0.01 RIC 1 vs. Control). Supporting findings were obtained from measurements of serum IL-10 as well as tissue malondialdehyde and ATP levels. Hemoxygenase-1 (HO-1) mRNA-expression was significantly higher in RIC 1 compared to Control (p<0.05 RIC 1 vs. Control). Conclusion These results suggest that RIC might confer potent protection against the detrimental effects of IR injury including tissue damage, apoptosis, graft circulation, inflammation, tissue energetic status in OLT. HO-1 overexpression might play an orchestrating role in RIC mediated organ protection. An earlier intervention (RIC 1 protocol) was more effective than remote conditioning after graft reperfusion.
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Affiliation(s)
- Zoltan Czigany
- Institute for Laboratory Animal Science and Experimental Surgery, RWTH-Aachen University, Aachen, Germany
- Department of Surgery and Transplantation, RWTH-Aachen University, Aachen, Germany
- * E-mail:
| | | | - Christian Beckers
- Department of Intensive Care Medicine, RWTH-Aachen University, Aachen, Germany
| | - Christian Stoppe
- Department of Intensive Care Medicine, RWTH-Aachen University, Aachen, Germany
| | - Michaela Möhring
- Institute for Laboratory Animal Science and Experimental Surgery, RWTH-Aachen University, Aachen, Germany
| | - Andras Fülöp
- HPB Research Center, 1st Department of Surgery, Semmelweis UniversityBudapest, Hungary
| | - Attila Szijarto
- HPB Research Center, 1st Department of Surgery, Semmelweis UniversityBudapest, Hungary
| | - Georg Lurje
- Department of Surgery and Transplantation, RWTH-Aachen University, Aachen, Germany
| | - Ulf P. Neumann
- Department of Surgery and Transplantation, RWTH-Aachen University, Aachen, Germany
| | - René H. Tolba
- Institute for Laboratory Animal Science and Experimental Surgery, RWTH-Aachen University, Aachen, Germany
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18
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Zhu R, Guo W, Fang H, Cao S, Yan B, Chen S, Zhang K, Zhang S. Kupffer cell depletion by gadolinium chloride aggravates liver injury after brain death in rats. Mol Med Rep 2018; 17:6357-6362. [PMID: 29488608 PMCID: PMC5928625 DOI: 10.3892/mmr.2018.8646] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Accepted: 02/08/2018] [Indexed: 12/25/2022] Open
Abstract
Brain death (BD) impairs liver function in potential donors, and is associated with hormonal and metabolic changes or molecular effects with pro‑inflammatory activation. Resident macrophages in the liver named Kupffer cells (KCs) undergo pro‑ or anti‑inflammatory pathway activation, which affects liver function. However, the role of the KCs in liver dysfunction following BD has not been fully elucidated. The aim of the present study was to investigate the role of KCs in liver dysfunction in the context of BD and the effects of their inhibition by gadolinium chloride (GdCl3). Rats were randomly divided into the following groups: Control, BD with GdCl3 pretreatment and BD with normal saline pretreatment. Liver function, hepatic pathological histology and cytokine levels in the liver were assessed. Apoptosis and apoptosis‑related proteins [cleaved caspase‑3, caspase‑3 and apoptosis regulator Bcl‑2 (Bcl‑2)] were evaluated. GdCl3 significantly aggravated liver injury by elevating alanine aminotransferase and aspartate aminotransferase levels (P<0.05) by inhibiting KCs. Interleukin (IL)‑1β and tumor necrosis factor α levels in the GdCl3 group were significantly increased compared with those in the control and saline groups (P<0.01). However, IL‑10 levels in the GdCl3 group were significantly reduced compared with those in the saline group (P<0.05). Caspase‑3 and cleaved caspase‑3 activation, and apoptosis induction in the context of BD were also significantly aggravated by the depletion of KCs, whereas Bcl‑2 was significantly suppressed by the administration of GdCl3. The present study indicated that GdCl3 efficiently inhibits the activity of KCs, and is involved in the onset of liver injury through its effects on pro‑inflammatory and anti‑inflammatory activation. KCs are protective in the liver in the context of BD. This protection appears to be due to KCs secretion of the potent anti‑inflammatory cytokine IL‑10, suggesting that KCs are an attractive target for the prevention and treatment of liver injury in the context of BD in rats.
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Affiliation(s)
- Rongtao Zhu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Weizhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Hongbo Fang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Shengli Cao
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Bing Yan
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Sanyang Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Kaiming Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Shuijun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
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Hirayama D, Iida T, Nakase H. The Phagocytic Function of Macrophage-Enforcing Innate Immunity and Tissue Homeostasis. Int J Mol Sci 2017; 19:E92. [PMID: 29286292 PMCID: PMC5796042 DOI: 10.3390/ijms19010092] [Citation(s) in RCA: 548] [Impact Index Per Article: 68.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 12/19/2017] [Accepted: 12/27/2017] [Indexed: 12/20/2022] Open
Abstract
Macrophages are effector cells of the innate immune system that phagocytose bacteria and secrete both pro-inflammatory and antimicrobial mediators. In addition, macrophages play an important role in eliminating diseased and damaged cells through their programmed cell death. Generally, macrophages ingest and degrade dead cells, debris, tumor cells, and foreign materials. They promote homeostasis by responding to internal and external changes within the body, not only as phagocytes, but also through trophic, regulatory, and repair functions. Recent studies demonstrated that macrophages differentiate from hematopoietic stem cell-derived monocytes and embryonic yolk sac macrophages. The latter mainly give rise to tissue macrophages. Macrophages exist in all vertebrate tissues and have dual functions in host protection and tissue injury, which are maintained at a fine balance. Tissue macrophages have heterogeneous phenotypes in different tissue environments. In this review, we focused on the phagocytic function of macrophage-enforcing innate immunity and tissue homeostasis for a better understanding of the role of tissue macrophages in several pathological conditions.
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Affiliation(s)
- Daisuke Hirayama
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Minami 1-jo Nishi 16-chome, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan.
| | - Tomoya Iida
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Minami 1-jo Nishi 16-chome, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan.
| | - Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Minami 1-jo Nishi 16-chome, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan.
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20
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MicroRNA-155 Deficiency in Kupffer Cells Ameliorates Liver Ischemia-Reperfusion Injury in Mice. Transplantation 2017. [PMID: 28640790 DOI: 10.1097/tp.0000000000001765] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND MicroRNA-155 (miR-155) is known to be involved in autoimmune diseases, inflammation, and transplantation. However, its role in a warm hepatic ischemia-reperfusion (IR) model has not been fully elucidated. METHODS Partial hepatic IR was performed in wild-type and miR-155-deficient mice treated with or without GdCl3, and then the serum transaminase concentration and histology were analyzed. Kupffer cells (KCs) were isolated from the liver after IR, and immunohistochemistry was used to evaluate activation and polarization. In addition, the mRNA concentrations of various inflammatory cytokines were measured. Macrophages were obtained from the abdominal cavity and challenged with or without lipopolysaccharide to determine the influence of miR-155 deficiency on macrophage polarization in vitro. Furthermore, we used in vitro coculture assays to determine the effect of miR-155 deficiency on hepatocyte apoptosis induced directly by KCs. RESULTS miR-155 deficiency ameliorated liver IR injury, and inhibition of KCs by GdCl3 abolished this protective effect. miR-155 deficiency decreased CD80, CD86, and major histocompatibility complex class II expression in KCs after IR and tipped the M1/M2 balance toward an anti-inflammatory profile, where proinflammatory cytokine secretion was suppressed and IL-10 was enhanced. In addition, hepatocyte apoptosis was reduced in coculture with miR-155-deficient KCs in vitro. CONCLUSIONS miR-155 deficiency plays an effective role in attenuating liver IR injury likely by regulating the activation and inflammatory response, as well as modifying the polarization of KCs.
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Świderska M, Jaroszewicz J, Stawicka A, Parfieniuk-Kowerda A, Chabowski A, Flisiak R. The interplay between Th17 and T-regulatory responses as well as adipokines in the progression of non-alcoholic fatty liver disease. Clin Exp Hepatol 2017; 3:127-134. [PMID: 29062902 PMCID: PMC5649483 DOI: 10.5114/ceh.2017.68466] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 02/07/2017] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a chronic progressive liver disease, coupled with metabolic syndrome, which may progress to non-alcoholic steatohepatitis (NASH). Diabetes, obesity, hypertension, hypercholesterolemia, and hypertriglyceridemia are considered to be the most common causes leading to the incidence of NAFLD. It is assumed that the accumulation of lipid deposits in hepatocytes leads to production of proinflammatory cytokines that triggers the development of liver inflammation. Regulatory T cells (Tregs) play a critical role in regulating inflammatory processes in NASH, while T helper type 17 (Th17) might functionally oppose Treg-mediated responses. In addition, important mediators of hepatic steatosis are fatty hormones known as adipokines. We aimed to describe the significance and interaction between Treg and Th17-related cytokines as well as adipokines in pathogenesis and its potential use as biomarkers of NAFLD, especially with respect to progression to NASH.
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Affiliation(s)
- Magdalena Świderska
- Department of Physiology, Medical University of Bialystok, Bialystok, Poland
| | - Jerzy Jaroszewicz
- Department of Infectious Diseases and Hepatology, Medical University of Silesia, Bytom, Poland
| | - Agnieszka Stawicka
- Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Bialystok, Poland
| | - Anna Parfieniuk-Kowerda
- Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Bialystok, Poland
| | - Adrian Chabowski
- Department of Physiology, Medical University of Bialystok, Bialystok, Poland
| | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Bialystok, Poland
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22
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Haga H, Yan IK, Borrelli DA, Matsuda A, Parasramka M, Shukla N, Lee DD, Patel T. Extracellular vesicles from bone marrow-derived mesenchymal stem cells protect against murine hepatic ischemia/reperfusion injury. Liver Transpl 2017; 23:791-803. [PMID: 28407355 PMCID: PMC5495137 DOI: 10.1002/lt.24770] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Accepted: 03/01/2017] [Indexed: 12/20/2022]
Abstract
Hepatic ischemia/reperfusion injury (IRI) and associated inflammation contributes to liver dysfunction and complications after liver surgery and transplantation. Mesenchymal stem cells (MSCs) have been reported to reduce hepatic IRI because of their reparative immunomodulatory effects in injured tissues. Recent studies have highlighted beneficial effects of extracellular vesicles from mesenchymal stem cells (MSC-EV) on tissue injury. The effects of systemically administered mouse bone marrow-derived MSC-EV were evaluated in an experimental murine model of hepatic IRI induced by cross-clamping the hepatic artery and portal vein for 90 minutes followed by reperfusion for periods of up to 6 hours. Compared with controls, intravenous administration of MSC-EV 30 minutes prior to IRI dramatically reduced the extent of tissue necrosis, decreased caspase 3-positive and apoptotic cells, and reduced serum aminotransferase levels. MSC-EV increased hepatic messenger RNA (mRNA) expression of NACHT, LRR, and PYD domains-containing protein 12, and the chemokine (C-X-C motif) ligand 1, and reduced mRNA expression of several inflammatory cytokines such as interleukin 6 during IRI. MSC-EV increased cell viability and suppressed both oxidative injury and nuclear factor kappa B activity in murine hepatocytes in vitro. In conclusion, the administration of extracellular vesicles derived from bone marrow-derived MSCs may ameliorate hepatic IRI by reducing hepatic injury through modulation of the inflammatory response.Liver Transplantation 23 791-803 2017 AASLD.
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Affiliation(s)
- Hiroaki Haga
- Departments of Transplantation and Cancer Biology; Mayo Clinic; Jacksonville Florida
| | - Irene K. Yan
- Departments of Transplantation and Cancer Biology; Mayo Clinic; Jacksonville Florida
| | - David A. Borrelli
- Departments of Transplantation and Cancer Biology; Mayo Clinic; Jacksonville Florida
| | - Akiko Matsuda
- Departments of Transplantation and Cancer Biology; Mayo Clinic; Jacksonville Florida
| | - Mansi Parasramka
- Departments of Transplantation and Cancer Biology; Mayo Clinic; Jacksonville Florida
| | - Neha Shukla
- Departments of Transplantation and Cancer Biology; Mayo Clinic; Jacksonville Florida
| | - David D. Lee
- Departments of Transplantation and Cancer Biology; Mayo Clinic; Jacksonville Florida
| | - Tushar Patel
- Departments of Transplantation and Cancer Biology; Mayo Clinic; Jacksonville Florida
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23
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Oldhafer F, Bock M, Falk CS, Vondran FWR. Immunological aspects of liver cell transplantation. World J Transplant 2016; 6:42-53. [PMID: 27011904 PMCID: PMC4801804 DOI: 10.5500/wjt.v6.i1.42] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Revised: 10/21/2015] [Accepted: 12/08/2015] [Indexed: 02/05/2023] Open
Abstract
Within the field of regenerative medicine, the liver is of major interest for adoption of regenerative strategies due to its well-known and unique regenerative capacity. Whereas therapeutic strategies such as liver resection and orthotopic liver transplantation (OLT) can be considered standards of care for the treatment of a variety of liver diseases, the concept of liver cell transplantation (LCTx) still awaits clinical breakthrough. Success of LCTx is hampered by insufficient engraftment/long-term acceptance of cellular allografts mainly due to rejection of transplanted cells. This is in contrast to the results achieved for OLT where long-term graft survival is observed on a regular basis and, hence, the liver has been deemed an immune-privileged organ. Immune responses induced by isolated hepatocytes apparently differ considerably from those observed following transplantation of solid organs and, thus, LCTx requires refined immunological strategies to improve its clinical outcome. In addition, clinical usage of LCTx but also related basic research efforts are hindered by the limited availability of high quality liver cells, strongly emphasizing the need for alternative cell sources. This review focuses on the various immunological aspects of LCTx summarizing data available not only for hepatocyte transplantation but also for transplantation of non-parenchymal liver cells and liver stem cells.
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