|
1
|
Nieuwenhuijs-Moeke GJ, Pischke SE, Berger SP, Sanders JSF, Pol RA, Struys MMRF, Ploeg RJ, Leuvenink HGD. Ischemia and Reperfusion Injury in Kidney Transplantation: Relevant Mechanisms in Injury and Repair. J Clin Med 2020; 9:jcm9010253. [PMID: 31963521 PMCID: PMC7019324 DOI: 10.3390/jcm9010253] [Citation(s) in RCA: 189] [Impact Index Per Article: 37.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 01/12/2020] [Accepted: 01/13/2020] [Indexed: 02/07/2023] Open
Abstract
Ischemia and reperfusion injury (IRI) is a complex pathophysiological phenomenon, inevitable in kidney transplantation and one of the most important mechanisms for non- or delayed function immediately after transplantation. Long term, it is associated with acute rejection and chronic graft dysfunction due to interstitial fibrosis and tubular atrophy. Recently, more insight has been gained in the underlying molecular pathways and signalling cascades involved, which opens the door to new therapeutic opportunities aiming to reduce IRI and improve graft survival. This review systemically discusses the specific molecular pathways involved in the pathophysiology of IRI and highlights new therapeutic strategies targeting these pathways.
Collapse
Affiliation(s)
- Gertrude J. Nieuwenhuijs-Moeke
- Department of Anesthesiology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands;
- Correspondence: ; Tel.: +31-631623075
| | - Søren E. Pischke
- Clinic for Emergencies and Critical Care, Department of Anesthesiology, Department of Immunology, Oslo University Hospital, 4950 Nydalen, 0424 Oslo, Norway;
| | - Stefan P. Berger
- Department of Nephrology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; (S.P.B.); (J.S.F.S.)
| | - Jan Stephan F. Sanders
- Department of Nephrology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; (S.P.B.); (J.S.F.S.)
| | - Robert A. Pol
- Department of Surgery, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; (R.A.P.); (R.J.P.); (H.G.D.L.)
| | - Michel M. R. F. Struys
- Department of Anesthesiology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands;
- Department of Basic and Applied Medical Sciences, Ghent University, Corneel Heymanslaan 10, 9000 Ghent, Belgium
| | - Rutger J. Ploeg
- Department of Surgery, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; (R.A.P.); (R.J.P.); (H.G.D.L.)
- Nuffield Department of Surgical Sciences, University of Oxford, Headington, Oxford OX3 9DU, UK
| | - Henri G. D. Leuvenink
- Department of Surgery, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; (R.A.P.); (R.J.P.); (H.G.D.L.)
| |
Collapse
|
|
2
|
Kwok C, Pavlosky A, Lian D, Jiang J, Huang X, Yin Z, Liu W, Haig A, Jevnikar AM, Zhang ZX. Necroptosis Is Involved in CD4+ T Cell-Mediated Microvascular Endothelial Cell Death and Chronic Cardiac Allograft Rejection. Transplantation 2017; 101:2026-2037. [PMID: 29633982 DOI: 10.1097/tp.0000000000001578] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Despite advances in immunosuppressive therapies, the rate of chronic transplant loss remains substantial. Organ injury involves various forms of cell death including apoptosis and necrosis. We now recognize that early injury of cardiac transplants involves a newly described form of programmed necrotic cell death, termed necroptosis. Because this involves receptor-interacting protein (RIP) kinase 1/3, this study aimed to establish the role of RIP3 in chronic cardiac allograft rejection. METHODS We used major histocompatibility complex class II mismatched C57BL/6N (H-2; B6) or B6.RIP3 (H-2; RIP3) mice to B6.C-H-2 (H2-Ab1; bm12) mouse cardiac transplantation. Microvascular endothelial cells (MVEC) were developed from B6 and RIP3 cardiac grafts. RESULT CD4 T cell-mediated cardiac graft rejection is inhibited using RIP3 deficient donor grafts, with reduced cellular infiltration and vasculopathy compared with wild type cardiac grafts. Alloreactive CD4 T cell-mediated MVEC death involves TNFα, Fas ligand (FasL) and granzyme B. Although necroptosis and release of danger molecule high-mobility group box 1 are eliminated by the absence of RIP3, CD4 T cells had attenuated MVEC death through granzyme B and FasL. CONCLUSIONS CD4 T cell-mediated MVEC death involves in TNFα, FasL and granzyme B. Necroptotic cell death and release of the danger molecule may promote inflammatory responses and transplant rejection. Although loss of RIP3 does not eliminate alloimmune responses, chronic graft injury is reduced. RIP3 is an important therapeutic target but additional granzyme and caspases inhibition is required for sufficiently improving long-term graft survival.
Collapse
Affiliation(s)
- Cecilia Kwok
- Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, London, Ontario, Canada
- Departments of Medicine, Pathology, Immunology, University of Western Ontario, London, Ontario, Canada
| | - Alexander Pavlosky
- Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, London, Ontario, Canada
- Departments of Medicine, Pathology, Immunology, University of Western Ontario, London, Ontario, Canada
| | - Dameng Lian
- Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, London, Ontario, Canada
| | - Jifu Jiang
- Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, London, Ontario, Canada
| | - Xuyan Huang
- Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, London, Ontario, Canada
| | - Ziqin Yin
- Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, London, Ontario, Canada
| | - Weihua Liu
- Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, London, Ontario, Canada
- Departments of Medicine, Pathology, Immunology, University of Western Ontario, London, Ontario, Canada
| | - Aaron Haig
- Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, London, Ontario, Canada
- Departments of Medicine, Pathology, Immunology, University of Western Ontario, London, Ontario, Canada
| | - Anthony M Jevnikar
- Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, London, Ontario, Canada
- Departments of Medicine, Pathology, Immunology, University of Western Ontario, London, Ontario, Canada
| | - Zhu-Xu Zhang
- Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, London, Ontario, Canada
- Departments of Medicine, Pathology, Immunology, University of Western Ontario, London, Ontario, Canada
| |
Collapse
|
|
3
|
Salvadori M, Rosso G, Bertoni E. Update on ischemia-reperfusion injury in kidney transplantation: Pathogenesis and treatment. World J Transplant 2015; 5:52-67. [PMID: 26131407 PMCID: PMC4478600 DOI: 10.5500/wjt.v5.i2.52] [Citation(s) in RCA: 259] [Impact Index Per Article: 25.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Revised: 01/16/2015] [Accepted: 04/27/2015] [Indexed: 02/05/2023] Open
Abstract
Ischemia/reperfusion injury is an unavoidable relevant consequence after kidney transplantation and influences short term as well as long-term graft outcome. Clinically ischemia/reperfusion injury is associated with delayed graft function, graft rejection, chronic rejection and chronic graft dysfunction. Ischemia/reperfusion affects many regulatory systems at the cellular level as well as in the renal tissue that result in a distinct inflammatory reaction of the kidney graft. Underlying factors of ischemia reperfusion include energy metabolism, cellular changes of the mitochondria and cellular membranes, initiation of different forms of cell death-like apoptosis and necrosis together with a recently discovered mixed form termed necroptosis. Chemokines and cytokines together with other factors promote the inflammatory response leading to activation of the innate immune system as well as the adaptive immune system. If the inflammatory reaction continues within the graft tissue, a progressive interstitial fibrosis develops that impacts long-term graft outcome. It is of particular importance in kidney transplantation to understand the underlying mechanisms and effects of ischemia/reperfusion on the graft as this knowledge also opens strategies to prevent or treat ischemia/reperfusion injury after transplantation in order to improve graft outcome.
Collapse
|
|
4
|
Salvadori M, Bertoni E. What's new in clinical solid organ transplantation by 2013. World J Transplant 2014; 4:243-266. [PMID: 25540734 PMCID: PMC4274595 DOI: 10.5500/wjt.v4.i4.243] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Revised: 07/11/2014] [Accepted: 07/27/2014] [Indexed: 02/05/2023] Open
Abstract
Innovative and exciting advances in the clinical science in solid organ transplantation continuously realize as the results of studies, clinical trials, international conferences, consensus conferences, new technologies and discoveries. This review will address to the full spectrum of news in transplantation, that verified by 2013. The key areas covered are the transplantation activity, with particular regards to the donors, the news for solid organs such as kidney, pancreas, liver, heart and lung, the news in immunosuppressive therapies, the news in the field of tolerance and some of the main complications following transplantation as infections and cancers. The period of time covered by the study starts from the international meetings held in 2012, whose results were published in 2013, up to the 2013 meetings, conferences and consensus published in the first months of 2014. In particular for every organ, the trends in numbers and survival have been reviewed as well as the most relevant problems such as organ preservation, ischemia reperfusion injuries, and rejections with particular regards to the antibody mediated rejection that involves all solid organs. The new drugs and strategies applied in organ transplantation have been divided into new way of using old drugs or strategies and drugs new not yet on the market, but on phase Ito III of clinical studies and trials.
Collapse
|
|
5
|
Saeed WK, Jun DW. Necroptosis: An emerging type of cell death in liver diseases. World J Gastroenterol 2014; 20:12526-12532. [PMID: 25253954 PMCID: PMC4168087 DOI: 10.3748/wjg.v20.i35.12526] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2013] [Revised: 06/03/2014] [Accepted: 07/16/2014] [Indexed: 02/06/2023] Open
Abstract
Cell death has been extensively evaluated for decades and it is well recognized that pharmacological interventions directed to inhibit cell death can prevent significant cell loss and can thus improve an organ’s physiological function. For long, only apoptosis was considered as a sole form of programmed cell death. Recently necroptosis, a RIP1/RIP3-dependent programmed cell death, has been identified as an apoptotic backup cell death mechanism with necrotic morphology. The evidences of necroptosis and protective effects achieved by blocking necroptosis have been extensively reported in recent past. However, only a few studies reported the evidence of necroptosis and protective effects achieved by inhibiting necroptosis in liver related disease conditions. Although the number of necroptosis initiators is increasing; however, interestingly, it is still unclear that what actually triggers necroptosis in different liver diseases or if there is always a different necroptosis initiator in each specific disease condition followed by specific downstream signaling molecules. Understanding the precise mechanism of necroptosis as well as counteracting other cell death pathways in liver diseases could provide a useful insight towards achieving extensive therapeutic significance. By targeting necroptosis and/or other parallel death pathways, a significant cell loss and thus a decrement in an organ’s physiological function can be prevented.
Collapse
|
|
6
|
Pavlosky A, Lau A, Su Y, Lian D, Huang X, Yin Z, Haig A, Jevnikar AM, Zhang ZX. RIPK3-mediated necroptosis regulates cardiac allograft rejection. Am J Transplant 2014; 14:1778-1790. [PMID: 24984764 DOI: 10.1111/ajt.12779] [Citation(s) in RCA: 156] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2014] [Revised: 04/02/2014] [Accepted: 04/04/2014] [Indexed: 01/25/2023]
Abstract
Cell death results in tissue damage and ultimately donor graft rejection and can occur as an active molecular process through apoptotic, necrotic and newly identified receptor interacting protein 1 and 3 kinase (RIPK1/3)-mediated necroptotic pathways. Necroptosis leads to the release of inflammatory molecules which can activate host immune cells. This pathway has yet to be studied in heart transplantation. We have found that necroptosis was induced in murine cardiac microvascular endothelial cell (MVEC) under anti-apoptotic condition following tumor necrosis factor alpha treatment. Necroptotic cell death and release of the danger molecule high mobility group box 1 (HMGB1) were inhibited by the RIPK1 inhibiting molecule necrostatin-1 and by genetic deletion of RIPK3. In addition, tissue necrosis, release of HMGB1 and graft cell infiltrate were attenuated in RIPK3 null heart allografts following transplantation. Finally, a brief sirolimus treatment markedly prolonged RIPK3 null cardiac allograft survival in allogeneic BALB/c recipients as compared to WT C57BL/6 donor grafts (95 ± 5.8 vs. 24 ± 2.6 days, p < 0.05). This study has demonstrated that RIPK1/3 contributes to MVEC death and cardiac allograft survival through necroptotic death and the release of danger molecules. Our results suggest that targeting RIPK-mediated necroptosis may be an important therapeutic strategy in transplantation.
Collapse
Affiliation(s)
- A Pavlosky
- Matthew Mailing Centre for Translational Transplantation Studies, Lawson Health Research Institute, London Health Sciences Centre, London, Ontario, Canada; Department of Pathology, Western University, London, Ontario, Canada
| | | | | | | | | | | | | | | | | |
Collapse
|