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Tielemans B, Van Slambrouck J, Özsoy B, Ceulemans LJ. Phenotyping of primary graft dysfunction after lung transplantation by in-depth biomarker analysis. ERJ Open Res 2024; 10:00439-2024. [PMID: 39104953 PMCID: PMC11299001 DOI: 10.1183/23120541.00439-2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 05/02/2024] [Indexed: 08/07/2024] Open
Abstract
This editorial highlights the importance of research towards PGD-specific biomarkers, suggesting strategic sample collection and advanced analysis techniques to expand our knowledge of PGD mechanisms and potential phenotyping https://bit.ly/3UUElw0.
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Affiliation(s)
- Birger Tielemans
- Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
- Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
| | - Jan Van Slambrouck
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium
- Department of Chronic Diseases and Metabolism, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
| | - Balin Özsoy
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium
- Department of Oncology, Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, KU Leuven, Leuven, Belgium
| | - Laurens J. Ceulemans
- Department of Thoracic Surgery, University Hospitals Leuven, Leuven, Belgium
- Department of Chronic Diseases and Metabolism, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium
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Gouchoe DA, Yi T, Kim JL, Lee YG, Black SM, Breuer C, Ma J, Whitson BA. MG53 mitigates warm ischemic lung injury in a murine model of transplantation. J Thorac Cardiovasc Surg 2024; 168:e13-e26. [PMID: 37925138 PMCID: PMC11998351 DOI: 10.1016/j.jtcvs.2023.10.056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 10/12/2023] [Accepted: 10/27/2023] [Indexed: 11/06/2023]
Abstract
OBJECTIVES Lung transplant warm ischemia-reperfusion injury (IRI) results in cellular injury, inflammation, and poor graft function. Mitsugumin 53 (MG53) is an endogenous protein with cell membrane repair properties and the ability to modulate the inflammasome. We hypothesize that the absence of circulating MG53 protein in the recipient increases IRI, and higher levels of circulating MG53 protein mitigate IRI associated with lung transplantation. METHODS To demonstrate protection, wild-type (wt) lung donor allografts were transplanted into a wt background, a MG53 knockout (mg53-/-), or a constitutively overexpressed MG53 (tissue plasminogen activator-MG53) recipient mouse after 1 hour of warm ischemic injury. Mice survived for 5 days after transplantation. Bronchioalveolar lavage, serum, and tissue were collected at sacrifice. Bronchioalveolar lavage, serum, and tissue markers of apoptosis and a biometric profile of lung health were analyzed. RESULTS mg53-/- mice had significantly greater levels of markers of overall cell lysis and endothelial cell injury. Overexpression of MG53 resulted in a signature similar to that of wt controls. At the time of explant, tissue plasminogen activator-MG53 recipient tissue expressed significantly greater levels of MG53, measured by immunohistochemistry, compared with mg53-/-, demonstrating uptake of endogenous overexpressed MG53 into donor tissue. CONCLUSIONS In a warm IRI model of lung transplantation, the absence of MG53 resulted in increased cell injury and inflammation. Endogenous overexpression of MG53 in the recipient results in protection in the wt donor. Together, these data suggest that MG53 is a potential therapeutic agent for use in lung transplantation to mitigate IRI.
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Affiliation(s)
- Doug A Gouchoe
- COPPER Lab (Collaboration for Organ Perfusion, Protection, Engineering, and Regeneration Laboratory), The Ohio State University, Columbus, Ohio; Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio; 88th Surgical Operations Squadron, Wright-Patterson Medical Center, Wright-Patterson AFB, Ohio
| | - Tai Yi
- Department of Surgery, Nationwide Children's Hospital, Columbus, Ohio
| | - Jung-Lye Kim
- COPPER Lab (Collaboration for Organ Perfusion, Protection, Engineering, and Regeneration Laboratory), The Ohio State University, Columbus, Ohio; Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Yong Gyu Lee
- COPPER Lab (Collaboration for Organ Perfusion, Protection, Engineering, and Regeneration Laboratory), The Ohio State University, Columbus, Ohio; Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Sylvester M Black
- COPPER Lab (Collaboration for Organ Perfusion, Protection, Engineering, and Regeneration Laboratory), The Ohio State University, Columbus, Ohio; Division of Transplantation, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | | | - Jianjie Ma
- Division of Surgical Sciences, Department of Surgery, University of Virginia Medical School, Charlottesville, Va
| | - Bryan A Whitson
- COPPER Lab (Collaboration for Organ Perfusion, Protection, Engineering, and Regeneration Laboratory), The Ohio State University, Columbus, Ohio; Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio; The Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical, College of Medicine, Columbus, Ohio.
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Gouchoe DA, Lee YG, Kim JL, Zhang Z, Marshall JM, Ganapathi A, Zhu H, Black SM, Ma J, Whitson BA. Mitsugumin 53 mitigation of ischemia-reperfusion injury in a mouse model. J Thorac Cardiovasc Surg 2024; 167:e48-e58. [PMID: 37562677 PMCID: PMC12047617 DOI: 10.1016/j.jtcvs.2023.08.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 07/14/2023] [Accepted: 08/01/2023] [Indexed: 08/12/2023]
Abstract
OBJECTIVE Primary graft dysfunction is often attributed to ischemia-reperfusion injury, and prevention would be a therapeutic approach to mitigate injury. Mitsugumin 53, a myokine, is a component of the endogenous cell membrane repair machinery. Previously, exogenous administration of recombinant human (recombinant human mitsugumin 53) protein has been shown to mitigate acute lung injury. In this study, we aimed to quantify a therapeutic benefit of recombinant human mitsugumin 53 to mitigate a transplant-relevant model of ischemia-reperfusion injury. METHODS C57BL/6J mice were subjected to 1 hour of ischemia (via left lung hilar clamp), followed by 24 hours of reperfusion. mg53-/- mice were administered exogenous recombinant human mitsugumin 53 or saline before reperfusion. Tissue, bronchoalveolar lavage, and blood samples were collected at death and used to quantify the extent of lung injury via histology and biochemical assays. RESULTS Administration of recombinant human mitsugumin 53 showed a significant decrease in an established biometric profile of lung injury as measured by lactate dehydrogenase and endothelin-1 in the bronchoalveolar lavage and plasma. Biochemical markers of apoptosis and pyroptosis (interleukin-1β and tumor necrosis factor-α) were also significantly mitigated, overall demonstrating recombinant human mitsugumin 53's ability to decrease the inflammatory response of ischemia-reperfusion injury. Exogenous recombinant human mitsugumin 53 administration showed a trend toward decreasing overall cellular infiltrate and neutrophil response. Fluorescent colocalization imaging revealed recombinant human mitsugumin 53 was effectively delivered to the endothelium. CONCLUSIONS These data demonstrate that recombinant human mitsugumin 53 has the potential to prevent or reverse ischemia-reperfusion injury-mediated lung damage. Although additional studies are needed in wild-type mice to demonstrate efficacy, this work serves as proof-of-concept to indicate the potential therapeutic benefit of mitsugumin 53 administration to mitigate ischemia-reperfusion injury.
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Affiliation(s)
- Doug A Gouchoe
- COPPER Lab (Collaboration for Organ Perfusion, Protection, Engineering, and Regeneration Laboratory), The Ohio State University, Columbus, Ohio; Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio; 88th Surgical Operations Squadron, Wright-Patterson Medical Center, WPAFB, Ohio
| | - Yong Gyu Lee
- COPPER Lab (Collaboration for Organ Perfusion, Protection, Engineering, and Regeneration Laboratory), The Ohio State University, Columbus, Ohio; Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Jung Lye Kim
- COPPER Lab (Collaboration for Organ Perfusion, Protection, Engineering, and Regeneration Laboratory), The Ohio State University, Columbus, Ohio; Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Zhentao Zhang
- Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Joanna M Marshall
- COPPER Lab (Collaboration for Organ Perfusion, Protection, Engineering, and Regeneration Laboratory), The Ohio State University, Columbus, Ohio; Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Asvin Ganapathi
- Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Hua Zhu
- Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Sylvester M Black
- COPPER Lab (Collaboration for Organ Perfusion, Protection, Engineering, and Regeneration Laboratory), The Ohio State University, Columbus, Ohio; Division of Transplantation, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Jianjie Ma
- Division of Surgical Sciences, Department of Surgery, University of Virginia Medical School, Charlottesville, Va
| | - Bryan A Whitson
- COPPER Lab (Collaboration for Organ Perfusion, Protection, Engineering, and Regeneration Laboratory), The Ohio State University, Columbus, Ohio; Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio; The Davis Heart and Lung Research Institute at The Ohio State University Wexner Medical, College of Medicine, Columbus, Ohio.
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Kim JL, Gouchoe DA, Reader BF, Dumond C, Lee YG, Black SM, Whitson BA. Biometric Profiling to Quantify Lung Injury Through Ex Vivo Lung Perfusion Following Warm Ischemia. ASAIO J 2023; 69:e368-e375. [PMID: 37192317 DOI: 10.1097/mat.0000000000001988] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/18/2023] Open
Abstract
Standard physiologic assessment parameters of donor lung grafts may not accurately reflect lung injury or quality. A biometric profile of ischemic injury could be identified as a means to assess the quality of the donor allograft. We sought to identify a biometric profile of lung ischemic injury assessed during ex vivo lung perfusion (EVLP). A rat model of lung donation after circulatory death (DCD) warm ischemic injury with subsequent EVLP evaluation was utilized. We did not observe a significant correlation between the classical physiological assessment parameters and the duration of the ischemic. In the perfusate, solubilized lactate dehydrogenase (LDH) as well as hyaluronic acid (HA) significantly correlated with duration of ischemic injury and length of perfusion ( p < 0.05). Similarly, in perfusates, the endothelin-1 (ET-1) and Big ET-1 correlated ischemic injury ( p < 0.05) and demonstrated a measure of endothelial cell injury. In tissue protein expression, heme oxygenase-1 (HO-1), angiopoietin 1 (Ang-1), and angiopoietin 2 (Ang-2) levels were correlated with the duration of ischemic injury ( p < 0.05). Cleaved caspase-3 levels were significantly elevated at 90 and 120 minutes ( p < 0.05) demonstrating increased apoptosis. A biometric profile of solubilized and tissue protein markers correlated with cell injury is a critical tool to aid in the evaluation of lung transplantation, as accurate evaluation of lung quality is imperative and improved quality leads to better results. http://links.lww.com/ASAIO/B49.
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Affiliation(s)
- Jung-Lye Kim
- From the Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio
- The Collaboration for Organ Perfusion, Protection, Engineering and Regeneration (COPPER) Laboratory, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Doug A Gouchoe
- From the Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio
- The Collaboration for Organ Perfusion, Protection, Engineering and Regeneration (COPPER) Laboratory, The Ohio State University Wexner Medical Center, Columbus, Ohio
- 88th Surgical Operations Squadron, Wright-Patterson Medical Center, Wright-Patterson AFB, Ohio
| | - Brenda F Reader
- From the Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio
- Comprehensive Transplant Center, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Curtis Dumond
- From the Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Yong Gyu Lee
- From the Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio
- The Collaboration for Organ Perfusion, Protection, Engineering and Regeneration (COPPER) Laboratory, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Sylvester M Black
- From the Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio
- The Collaboration for Organ Perfusion, Protection, Engineering and Regeneration (COPPER) Laboratory, The Ohio State University Wexner Medical Center, Columbus, Ohio
- Comprehensive Transplant Center, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Bryan A Whitson
- From the Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio
- The Collaboration for Organ Perfusion, Protection, Engineering and Regeneration (COPPER) Laboratory, The Ohio State University Wexner Medical Center, Columbus, Ohio
- Comprehensive Transplant Center, The Ohio State University Wexner Medical Center, Columbus, Ohio
- The Davis Heart and Lung Research Institute at The Ohio State University Wexner Medical, College of Medicine, Columbus, Ohio
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Avtaar Singh SS, Das De S, Al-Adhami A, Singh R, Hopkins PMA, Curry PA. Primary graft dysfunction following lung transplantation: From pathogenesis to future frontiers. World J Transplant 2023; 13:58-85. [PMID: 36968136 PMCID: PMC10037231 DOI: 10.5500/wjt.v13.i3.58] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 11/11/2022] [Accepted: 02/17/2023] [Indexed: 03/16/2023] Open
Abstract
Lung transplantation is the treatment of choice for patients with end-stage lung disease. Currently, just under 5000 lung transplants are performed worldwide annually. However, a major scourge leading to 90-d and 1-year mortality remains primary graft dysfunction. It is a spectrum of lung injury ranging from mild to severe depending on the level of hypoxaemia and lung injury post-transplant. This review aims to provide an in-depth analysis of the epidemiology, patho physiology, risk factors, outcomes, and future frontiers involved in mitigating primary graft dysfunction. The current diagnostic criteria are examined alongside changes from the previous definition. We also highlight the issues surrounding chronic lung allograft dysfunction and identify the novel therapies available for ex-vivo lung perfusion. Although primary graft dysfunction remains a significant contributor to 90-d and 1-year mortality, ongoing research and development abreast with current technological advancements have shed some light on the issue in pursuit of future diagnostic and therapeutic tools.
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Affiliation(s)
- Sanjeet Singh Avtaar Singh
- Department of Cardiothoracic Surgery, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, United Kingdom
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom
| | - Sudeep Das De
- Heart and Lung Transplant Unit, Wythenshawe Hospital, Manchester M23 9NJ, United Kingdom
| | - Ahmed Al-Adhami
- Department of Cardiothoracic Surgery, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, United Kingdom
- Department of Heart and Lung Transplant, Royal Papworth Hospital, Cambridge CB2 0AY, United Kingdom
| | - Ramesh Singh
- Mechanical Circulatory Support, Inova Health System, Falls Church, VA 22042, United States
| | - Peter MA Hopkins
- Queensland Lung Transplant Service, Prince Charles Hospital, Brisbane, QLD 4032, Australia
| | - Philip Alan Curry
- Department of Cardiothoracic Surgery, Golden Jubilee National Hospital, Glasgow G81 4DY, United Kingdom
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Hernández-Jiménez C, Olmos-Zúñiga JR, Baltazares-Lipp M, Jasso-Victoria R, Polo-Jerez A, Pérez-López MT, Vázquez-Justiniano LF, Díaz-Martínez NE, Gaxiola-Gaxiola M, Romero-Romero L, Guzmán-Cedillo AE, Baltazares-Lipp ME, Vázquez-Minero JC, Gutiérrez-González LH, Alonso-Gómez M, Silva-Martínez M. Endothelin-Converting Enzyme 1 and Vascular Endothelial Growth Factor as Potential Biomarkers during Ex Vivo Lung Perfusion with Prolonged Hypothermic Lung-Sparing. DISEASE MARKERS 2022; 2022:6412238. [PMID: 35178130 PMCID: PMC8844163 DOI: 10.1155/2022/6412238] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 01/04/2022] [Accepted: 01/06/2022] [Indexed: 12/18/2022]
Abstract
Lung transplantation requires optimization of donor's organ use through ex vivo lung perfusion (EVLP) to avoid primary graft dysfunction. Biomarkers can aid in organ selection by providing early evidence of suboptimal lungs during EVLP and thus avoid high-risk transplantations. However, predictive biomarkers of pulmonary graft function such as endothelin-converting enzyme (ECE-1) and vascular endothelial growth factor (VEGF) have not been described under EVLP with standard prolonged hypothermic preservation, which are relevant in situations where lung procurement is difficult or far from the transplantation site. Therefore, this study is aimed at quantifying ECE-1 and VEGF, as well as determining their association with hemodynamic, gasometric, and mechanical ventilatory parameters in a swine model of EVLP with standard prolonged hypothermic preservation. Using a protocol with either immediate (I-) or delayed (D-) initiation of EVLP, ECE-1 levels over time were found to remain constant in both study groups (p > 0.05 RM-ANOVA), while the VEGF protein was higher after prolonged preservation, but it decreased throughout EVLP (p > 0.05 RM-ANOVA). Likewise, hemodynamic, gasometric, mechanical ventilatory, and histological parameters had a tendency to better results after 12 hours of hypothermic preservation in the delayed infusion group.
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Affiliation(s)
- Claudia Hernández-Jiménez
- Department of Surgical Research, National Institute of Respiratory Diseases Ismael Cosío Villegas, Mexico City, Mexico
| | - J. Raúl Olmos-Zúñiga
- Experimental Lung Transplant Unit, National Institute of Respiratory Diseases Ismael Cosío Villegas, Mexico City, Mexico
| | - Matilde Baltazares-Lipp
- Department of Surgical Research, National Institute of Respiratory Diseases Ismael Cosío Villegas, Mexico City, Mexico
| | - Rogelio Jasso-Victoria
- Department of Surgical Research, National Institute of Respiratory Diseases Ismael Cosío Villegas, Mexico City, Mexico
| | - Adrián Polo-Jerez
- Department of Surgical Research, National Institute of Respiratory Diseases Ismael Cosío Villegas, Mexico City, Mexico
| | - María Teresa Pérez-López
- Nursing Research Coordination, National Institute of Respiratory Diseases Ismael Cosío Villegas, Mexico City, Mexico
| | | | - Néstor Emmanuel Díaz-Martínez
- Laboratory of Cellular Reprogramming and Tissue Engineering, Department of Medical and Pharmaceutical Biotechnology, Center for Research and Assistance in Technology and Design of the State of Jalisco, A.C, Mexico City, Mexico
| | - Miguel Gaxiola-Gaxiola
- Laboratory of Morphology, National Institute of Respiratory Diseases Ismael Cosío Villegas, Mexico City, Mexico
| | - Laura Romero-Romero
- Department of Pathology, School of Veterinary Medicine and Zootechnics, UNAM, Mexico City, Mexico
| | - Axel Edmundo Guzmán-Cedillo
- Department of Surgical Research, National Institute of Respiratory Diseases Ismael Cosío Villegas, Mexico City, Mexico
| | - Mario Enrique Baltazares-Lipp
- Hemodynamics and Echocardiography Service, National Institute of Respiratory Diseases Ismael Cosío Villegas, Mexico City, Mexico
| | - Juan Carlos Vázquez-Minero
- Cardiothoracic Surgery Service, National Institute of Respiratory Diseases Ismael Cosío Villegas, Mexico City, Mexico
| | | | - Marcelino Alonso-Gómez
- Department of Surgical Research, National Institute of Respiratory Diseases Ismael Cosío Villegas, Mexico City, Mexico
| | - Mariana Silva-Martínez
- Experimental Lung Transplant Unit, National Institute of Respiratory Diseases Ismael Cosío Villegas, Mexico City, Mexico
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Walweel K, Boon AC, See Hoe LE, Obonyo NG, Pedersen SE, Diab SD, Passmore MR, Hyslop K, Colombo SM, Bartnikowski NJ, Bouquet M, Wells MA, Black DM, Pimenta LP, Stevenson AK, Bisht K, Skeggs K, Marshall L, Prabhu A, James LN, Platts DG, Macdonald PS, McGiffin DC, Suen JY, Fraser JF. Brain stem death induces pro-inflammatory cytokine production and cardiac dysfunction in sheep model. Biomed J 2021; 45:776-787. [PMID: 34666219 PMCID: PMC9661508 DOI: 10.1016/j.bj.2021.10.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 08/12/2021] [Accepted: 10/07/2021] [Indexed: 11/23/2022] Open
Abstract
Introduction Organs procured following brain stem death (BSD) are the main source of organ grafts for transplantation. However, BSD is associated with inflammatory responses that may damage the organ and affect both the quantity and quality of organs available for transplant. Therefore, we aimed to investigate plasma and bronchoalveolar lavage (BAL) pro-inflammatory cytokine profiles and cardiovascular physiology in a clinically relevant 6-h ovine model of BSD. Methods Twelve healthy female sheep (37–42 Kg) were anaesthetized and mechanically ventilated prior to undergoing BSD induction and then monitored for 6 h. Plasma and BAL endothelin-1 and cytokines (IL-1β, 6, 8 and tumour necrosis factor alpha (TNF-α)) were assessed by ELISA. Differential white blood cell counts were performed. Cardiac function during BSD was also examined using echocardiography, and cardiac biomarkers (A-type natriuretic peptide and troponin I were measured in plasma. Results Plasma concentrations big ET-1, IL-6, IL-8, TNF-α and BAL IL-8 were significantly (p < 0.01) increased over baseline at 6 h post-BSD. Increased numbers of neutrophils were observed in the whole blood (3.1 × 109 cells/L [95% confidence interval (CI) 2.06–4.14] vs. 6 × 109 cells/L [95%CI 3.92–7.97]; p < 0.01) and BAL (4.5 × 109 cells/L [95%CI 0.41–9.41] vs. 26 [95%CI 12.29–39.80]; p = 0.03) after 6 h of BSD induction vs baseline. A significant increase in ANP production (20.28 pM [95%CI 16.18–24.37] vs. 78.68 pM [95%CI 53.16–104.21]; p < 0.0001) and cTnI release (0.039 ng/mL vs. 4.26 [95%CI 2.69–5.83] ng/mL; p < 0.0001), associated with a significant reduction in heart contractile function, were observed between baseline and 6 h. Conclusions BSD induced systemic pro-inflammatory responses, characterized by increased neutrophil infiltration and cytokine production in the circulation and BAL fluid, and associated with reduced heart contractile function in ovine model of BSD.
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Affiliation(s)
- K Walweel
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia.
| | - A C Boon
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia
| | - L E See Hoe
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia
| | - N G Obonyo
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia; Initiative to Develop African Research Leaders, KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya
| | - S E Pedersen
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia
| | - S D Diab
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia
| | - M R Passmore
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia
| | - K Hyslop
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia
| | - S M Colombo
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia; University of Milan, Italy
| | | | - M Bouquet
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia
| | - M A Wells
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia; School of Medical Science, Griffith University, Australia
| | - D M Black
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia
| | - L P Pimenta
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia
| | - A K Stevenson
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia
| | - K Bisht
- Mater Research Institute, University of Queensland, Australia
| | - K Skeggs
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia; Princess Alexandra Hospital, Woolloongabba, Brisbane, Australia
| | - L Marshall
- Princess Alexandra Hospital, Woolloongabba, Brisbane, Australia
| | - A Prabhu
- The Prince Charles Hospital, Rode Road, Brisbane, Australia
| | - L N James
- Princess Alexandra Hospital, Woolloongabba, Brisbane, Australia
| | - D G Platts
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia
| | - P S Macdonald
- Cardiac Mechanics Research Laboratory, St. Vincent's Hospital and the Victor Chang Cardiac Research Institute, Victoria Street, Darlinghurst, Sydney, Australia
| | - D C McGiffin
- Cardiothoracic Surgery and Transplantation, The Alfred Hospital, Melbourne, Australia
| | - J Y Suen
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia.
| | - J F Fraser
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia.
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Patel PM, Connolly MR, Coe TM, Calhoun A, Pollok F, Markmann JF, Burdorf L, Azimzadeh A, Madsen JC, Pierson RN. Minimizing Ischemia Reperfusion Injury in Xenotransplantation. Front Immunol 2021; 12:681504. [PMID: 34566955 PMCID: PMC8458821 DOI: 10.3389/fimmu.2021.681504] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 08/12/2021] [Indexed: 12/21/2022] Open
Abstract
The recent dramatic advances in preventing "initial xenograft dysfunction" in pig-to-non-human primate heart transplantation achieved by minimizing ischemia suggests that ischemia reperfusion injury (IRI) plays an important role in cardiac xenotransplantation. Here we review the molecular, cellular, and immune mechanisms that characterize IRI and associated "primary graft dysfunction" in allotransplantation and consider how they correspond with "xeno-associated" injury mechanisms. Based on this analysis, we describe potential genetic modifications as well as novel technical strategies that may minimize IRI for heart and other organ xenografts and which could facilitate safe and effective clinical xenotransplantation.
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Affiliation(s)
- Parth M. Patel
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Margaret R. Connolly
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Taylor M. Coe
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Anthony Calhoun
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
- Department of Surgery, Division of Cardiac Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Franziska Pollok
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
- Department of Anesthesiology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - James F. Markmann
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
- Department of Surgery, Division of Transplantation, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Lars Burdorf
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
- Department of Surgery, Division of Cardiac Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Agnes Azimzadeh
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
- Department of Surgery, Division of Cardiac Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Joren C. Madsen
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
- Department of Surgery, Division of Cardiac Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Richard N. Pierson
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
- Department of Surgery, Division of Cardiac Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
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9
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Abstract
Primary graft dysfunction (PGD) is a form of acute lung injury after transplantation characterized by hypoxemia and the development of alveolar infiltrates on chest radiograph that occurs within 72 hours of reperfusion. PGD is among the most common early complications following lung transplantation and significantly contributes to increased short-term morbidity and mortality. In addition, severe PGD has been associated with higher 90-day and 1-year mortality rates compared with absent or less severe PGD and is a significant risk factor for the subsequent development of chronic lung allograft dysfunction. The International Society for Heart and Lung Transplantation released updated consensus guidelines in 2017, defining grade 3 PGD, the most severe form, by the presence of alveolar infiltrates and a ratio of PaO2:FiO2 less than 200. Multiple donor-related, recipient-related, and perioperative risk factors for PGD have been identified, many of which are potentially modifiable. Consistently identified risk factors include donor tobacco and alcohol use; increased recipient body mass index; recipient history of pulmonary hypertension, sarcoidosis, or pulmonary fibrosis; single lung transplantation; and use of cardiopulmonary bypass, among others. Several cellular pathways have been implicated in the pathogenesis of PGD, thus presenting several possible therapeutic targets for preventing and treating PGD. Notably, use of ex vivo lung perfusion (EVLP) has become more widespread and offers a potential platform to safely investigate novel PGD treatments while expanding the lung donor pool. Even in the presence of significantly prolonged ischemic times, EVLP has not been associated with an increased risk for PGD.
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Affiliation(s)
- Jake G Natalini
- Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.,Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Joshua M Diamond
- Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
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10
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Yang S, Abuduwufuer A, Lv W, Bao F, Hu J. [Predictors for the Bronchiolitis Obliterans Syndrome in Lung Transplant Patient]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2020; 23:496-502. [PMID: 32517455 PMCID: PMC7309540 DOI: 10.3779/j.issn.1009-3419.2020.101.03] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
肺移植是治疗终末期肺病的有效方法。目前，肺移植术后1年生存率已达到80%，由于闭塞性细支气管炎综合症（bronchiolitis obliterans syndrome, BOS）的发生，5年生存率维持在50%左右。BOS是一个纤维化的过程，最终导致不可逆的气道闭塞。缺血-再灌注损伤、感染、氧化应激以及急性排斥反应等多个因素参与了BOS的发生。研究证实BOS的早期诊断与预后良好相关。因此，寻找灵敏、特异的BOS预测标记物对于提高肺移植患者长期生存具有重要的科学和临床意义。本文就与BOS发生发展相关的免疫调节细胞、分泌性蛋白质、细胞膜蛋白等指标的变化在BOS早期诊断中的作用进行综述。
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Affiliation(s)
- Sijia Yang
- The First Affiliated Hospital, Collage of Medicine, Zhejiang University, Hangzhou 310003, China
| | | | - Wang Lv
- The First Affiliated Hospital, Collage of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Feichao Bao
- The First Affiliated Hospital, Collage of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Jian Hu
- The First Affiliated Hospital, Collage of Medicine, Zhejiang University, Hangzhou 310003, China
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11
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Endothelial Glycocalyx Shedding Predicts Donor Organ Acceptability and Is Associated With Primary Graft Dysfunction in Lung Transplant Recipients. Transplantation 2019; 103:1277-1285. [DOI: 10.1097/tp.0000000000002539] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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12
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Mansournia MA, Geroldinger A, Greenland S, Heinze G. Separation in Logistic Regression: Causes, Consequences, and Control. Am J Epidemiol 2018; 187:864-870. [PMID: 29020135 DOI: 10.1093/aje/kwx299] [Citation(s) in RCA: 137] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Accepted: 08/03/2017] [Indexed: 11/12/2022] Open
Abstract
Separation is encountered in regression models with a discrete outcome (such as logistic regression) where the covariates perfectly predict the outcome. It is most frequent under the same conditions that lead to small-sample and sparse-data bias, such as presence of a rare outcome, rare exposures, highly correlated covariates, or covariates with strong effects. In theory, separation will produce infinite estimates for some coefficients. In practice, however, separation may be unnoticed or mishandled because of software limits in recognizing and handling the problem and in notifying the user. We discuss causes of separation in logistic regression and describe how common software packages deal with it. We then describe methods that remove separation, focusing on the same penalized-likelihood techniques used to address more general sparse-data problems. These methods improve accuracy, avoid software problems, and allow interpretation as Bayesian analyses with weakly informative priors. We discuss likelihood penalties, including some that can be implemented easily with any software package, and their relative advantages and disadvantages. We provide an illustration of ideas and methods using data from a case-control study of contraceptive practices and urinary tract infection.
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Affiliation(s)
- Mohammad Ali Mansournia
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Angelika Geroldinger
- Section for Clinical Biometrics, Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Austria
| | - Sander Greenland
- Department of Epidemiology, Fielding School of Public Health, University of California Los Angeles, Los Angeles, California
- Department of Statistics, University of California Los Angeles, Los Angeles, California
| | - Georg Heinze
- Section for Clinical Biometrics, Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Austria
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13
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Hamilton BCS, Dincheva GR, Zhuo H, Golden JA, Brzezinski M, Singer JP, Matthay MA, Kukreja J. Elevated donor plasminogen activator inhibitor-1 levels and the risk of primary graft dysfunction. Clin Transplant 2018; 32:e13210. [PMID: 29377268 DOI: 10.1111/ctr.13210] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/22/2018] [Indexed: 01/11/2023]
Abstract
Primary graft dysfunction (PGD) following lung transplantation is associated with elevated recipient plasma levels of plasminogen activator inhibitor-1 (PAI-1) and the receptor for advanced glycation end products (RAGE). However, the significance of these biomarkers in the donor plasma is uncertain. We hypothesized that elevated donor plasma levels of PAI-1 and RAGE would be associated with recipient PGD. We carried out a prospective unmatched case-control study of double-lung transplant recipients between May 2014 and September 2015. We compared donor plasma levels of PAI-1 and RAGE using rank-sum tests and t tests, in 12 recipients who developed PGD grade 2 or 3 within 72 hours postoperatively with 13 recipients who did not. Recipients who developed PGD had higher donor plasma levels of PAI-1 than recipients who did not (median 2.7 ng/mL vs 1.4; P = .03). Recipients with PGD also had numerically higher donor plasma levels of RAGE than recipients without PGD, although this difference did not achieve statistical significance (median 1061 pg/mL vs 679; P = .12). Systemic inflammatory responses in the donor, as reflected by elevated plasma levels of PAI-1, may contribute to the risk of developing PGD. Rapid biomarker assessment of easily available plasma samples may assist in donor lung selection and risk stratification.
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Affiliation(s)
| | | | - Hanjing Zhuo
- Department of Surgery, University of California, San Francisco, CA, USA
| | - Jeffrey A Golden
- Department of Surgery, University of California, San Francisco, CA, USA
| | - Marek Brzezinski
- Department of Surgery, University of California, San Francisco, CA, USA
| | - Jonathan P Singer
- Department of Surgery, University of California, San Francisco, CA, USA
| | - Michael A Matthay
- Department of Surgery, University of California, San Francisco, CA, USA
| | - Jasleen Kukreja
- Department of Surgery, University of California, San Francisco, CA, USA
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14
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Abstract
Primary graft dysfunction is a form of acute injury after lung transplantation that is associated with significant short- and long-term morbidity and mortality. Multiple mechanisms contribute to the pathogenesis of primary graft dysfunction, including ischemia reperfusion injury, epithelial cell death, endothelial cell dysfunction, innate immune activation, oxidative stress, and release of inflammatory cytokines and chemokines. This article reviews the epidemiology, pathogenesis, risk factors, prevention, and treatment of primary graft dysfunction.
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Affiliation(s)
- Mary K Porteous
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, 423 Guardian Drive, Philadelphia, PA 19104, USA.
| | - James C Lee
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA
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15
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Hamilton BCS, Kukreja J, Ware LB, Matthay MA. Protein biomarkers associated with primary graft dysfunction following lung transplantation. Am J Physiol Lung Cell Mol Physiol 2017; 312:L531-L541. [PMID: 28130262 DOI: 10.1152/ajplung.00454.2016] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Revised: 01/23/2017] [Accepted: 01/23/2017] [Indexed: 12/13/2022] Open
Abstract
Severe primary graft dysfunction affects 15-20% of lung transplant recipients and carries a high mortality risk. In addition to known donor, recipient, and perioperative clinical risk factors, numerous biologic factors are thought to contribute to primary graft dysfunction. Our current understanding of the pathogenesis of lung injury and primary graft dysfunction emphasizes multiple pathways leading to lung endothelial and epithelial injury. Protein biomarkers specific to these pathways can be measured in the plasma, bronchoalveolar lavage fluid, and lung tissue. Clarification of the pathophysiology and timing of primary graft dysfunction could illuminate predictors of dysfunction, allowing for better risk stratification, earlier identification of susceptible recipients, and development of targeted therapies. Here, we review much of what has been learned about the association of protein biomarkers with primary graft dysfunction and evaluate this association at different measurement time points.
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Affiliation(s)
- B C S Hamilton
- Department of Surgery, University of California San Francisco, San Francisco, California;
| | - J Kukreja
- Department of Surgery, University of California San Francisco, San Francisco, California
| | - L B Ware
- Department of Medicine and Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - M A Matthay
- Department of Medicine, Anesthesia, and the Cardiovascular Research Institute, University of California San Francisco, San Francisco, California; and
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16
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Watts RP, Bilska I, Diab S, Dunster KR, Bulmer AC, Barnett AG, Fraser JF. Novel 24-h ovine model of brain death to study the profile of the endothelin axis during cardiopulmonary injury. Intensive Care Med Exp 2015; 3:31. [PMID: 26596583 PMCID: PMC4656265 DOI: 10.1186/s40635-015-0067-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Accepted: 11/13/2015] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND Upregulation of the endothelin axis has been observed in pulmonary tissue after brain death, contributing to primary graft dysfunction and ischaemia reperfusion injury. The current study aimed to develop a novel, 24-h, clinically relevant, ovine model of brain death to investigate the profile of the endothelin axis during brain death-associated cardiopulmonary injury. We hypothesised that brain death in sheep would also result in demonstrable injury to other transplantable organs. METHODS Twelve merino cross ewes were randomised into two groups. Following induction of general anaesthesia and placement of invasive monitoring, brain death was induced in six animals by inflation of an extradural catheter. All animals were supported in an intensive care unit environment for 24 h. Animal management reflected current human donor management, including administration of vasopressors, inotropes and hormone resuscitation therapy. Activation of the endothelin axis and transplantable organ injury were assessed using ELISA, immunohistochemistry and standard biochemical markers. RESULTS All animals were successfully supported for 24 h. ELISA suggested early endothelin-1 and big endothelin-1 release, peaking 1 and 6 h after BD, respectively, but there was no difference at 24 h. Immunohistochemistry confirmed the presence of the endothelin axis in pulmonary tissue. Brain dead animals demonstrated tachycardia and hypertension, followed by haemodynamic collapse, typified by a reduction in systemic vascular resistance to 46 ± 1 % of baseline. Mean pulmonary artery pressure rose to 186 ± 20 % of baseline at induction and remained elevated throughout the protocol, reaching 25 ± 2.2 mmHg at 24 h. Right ventricular stroke work increased 25.9 % above baseline by 24 h. Systemic markers of cardiac and hepatocellular injury were significantly elevated, with no evidence of renal dysfunction. CONCLUSIONS This novel, clinically relevant, ovine model of brain death demonstrated that increased pulmonary artery pressures are observed after brain death. This may contribute to right ventricular dysfunction and pulmonary injury. The development of this model will allow for further investigation of therapeutic strategies to minimise the deleterious effects of brain death on potentially transplantable organs.
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Affiliation(s)
- Ryan P Watts
- Critical Care Research Group, The Prince Charles Hospital, Chermside, Queensland, Australia.
- University of Queensland, Brisbane, Queensland, Australia.
- Royal Brisbane and Women's Hospital, Herston, Queensland, Australia.
| | - Izabela Bilska
- Critical Care Research Group, The Prince Charles Hospital, Chermside, Queensland, Australia.
- Heart Foundation Research Centre, Griffith Health Institute, Griffith University, Southport, Queensland, Australia.
| | - Sara Diab
- Critical Care Research Group, The Prince Charles Hospital, Chermside, Queensland, Australia.
| | - Kimble R Dunster
- Critical Care Research Group, The Prince Charles Hospital, Chermside, Queensland, Australia.
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
| | - Andrew C Bulmer
- Heart Foundation Research Centre, Griffith Health Institute, Griffith University, Southport, Queensland, Australia.
| | - Adrian G Barnett
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
| | - John F Fraser
- Critical Care Research Group, The Prince Charles Hospital, Chermside, Queensland, Australia.
- Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
- University of Queensland, Brisbane, Queensland, Australia.
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17
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Porteous MK, Diamond JM, Christie JD. Primary graft dysfunction: lessons learned about the first 72 h after lung transplantation. Curr Opin Organ Transplant 2015; 20:506-14. [PMID: 26262465 PMCID: PMC4624097 DOI: 10.1097/mot.0000000000000232] [Citation(s) in RCA: 96] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PURPOSE OF REVIEW In 2005, the International Society for Heart and Lung Transplantation published a standardized definition of primary graft dysfunction (PGD), facilitating new knowledge on this form of acute lung injury that occurs within 72 h of lung transplantation. PGD continues to be associated with significant morbidity and mortality. This article will summarize the current literature on the epidemiology of PGD, pathogenesis, risk factors, and preventive and treatment strategies. RECENT FINDINGS Since 2011, several manuscripts have been published that provide insight into the clinical risk factors and pathogenesis of PGD. In addition, several transplant centers have explored preventive and treatment strategies for PGD, including the use of extracorporeal strategies. More recently, results from several trials assessing the role of extracorporeal lung perfusion may allow for much-needed expansion of the donor pool, without raising PGD rates. SUMMARY This article will highlight the current state of the science regarding PGD, focusing on recent advances, and set a framework for future preventive and treatment strategies.
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Affiliation(s)
- Mary K Porteous
- aDepartment of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA bCenter for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
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18
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Machuca TN, Cypel M, Zhao Y, Grasemann H, Tavasoli F, Yeung JC, Bonato R, Chen M, Zamel R, Chun YM, Guan Z, de Perrot M, Waddell TK, Liu M, Keshavjee S. The role of the endothelin-1 pathway as a biomarker for donor lung assessment in clinical ex vivo lung perfusion. J Heart Lung Transplant 2015; 34:849-57. [DOI: 10.1016/j.healun.2015.01.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Revised: 11/27/2014] [Accepted: 01/13/2015] [Indexed: 11/15/2022] Open
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19
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Abstract
OBJECTIVES To study the impact of ex vivo lung perfusion (EVLP) on cytokines, chemokines, and growth factors and their correlation with graft performance either during perfusion or after transplantation. BACKGROUND EVLP is a modern technique that preserves lungs on normothermia in a metabolically active state. The identification of biomarkers during clinical EVLP can contribute to the safe expansion of the donor pool. METHODS High-risk brain death donors and donors after cardiac death underwent 4 to 6 hours EVLP. Using a multiplex magnetic bead array assay, we evaluated analytes in perfusate samples collected at 1 hour and 4 hours of EVLP. Donor lungs were divided into 3 groups: (I) Control: bilateral transplantation with good early outcome [absence of primary graft dysfunction- (PGD) grade 3]; (II) PGD3: bilateral transplantation with PGD grade 3 anytime within 72 hours; (III) Declined: lungs unsuitable for transplantation after EVLP. RESULTS Of 50 cases included in this study, 27 were in Control group, 7 in PGD3, and 16 in Declined. From a total of 51 analytes, 34 were measurable in perfusates. The best marker to differentiate declined lungs from control lungs was stem cell growth factor -β [P < 0.001, AUC (area under the curve) = 0.86] at 1 hour. The best markers to differentiate PGD3 cases from controls were interleukin-8 (P < 0.001, AUC = 0.93) and growth-regulated oncogene-α (P = 0.001, AUC = 0.89) at 4 hours of EVLP. CONCLUSIONS Perfusate protein expression during EVLP can differentiate lungs with good outcome from lungs PGD3 after transplantation. These perfusate biomarkers can be potentially used for more precise donor lung selection improving the outcomes of transplantation.
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20
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Abstract
Primary graft dysfunction (PGD) is a syndrome encompassing a spectrum of mild to severe lung injury that occurs within the first 72 hours after lung transplantation. PGD is characterized by pulmonary edema with diffuse alveolar damage that manifests clinically as progressive hypoxemia with radiographic pulmonary infiltrates. In recent years, new knowledge has been generated on risks and mechanisms of PGD. Following ischemia and reperfusion, inflammatory and immunological injury-repair responses appear to be key controlling mechanisms. In addition, PGD has a significant impact on short- and long-term outcomes; therefore, the choice of donor organ is impacted by this potential adverse consequence. Improved methods of reducing PGD risk and efforts to safely expand the pool are being developed. Ex vivo lung perfusion is a strategy that may improve risk assessment and become a promising platform to implement treatment interventions to prevent PGD. This review details recent updates in the epidemiology, pathophysiology, molecular and genetic biomarkers, and state-of-the-art technical developments affecting PGD.
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Affiliation(s)
- Yoshikazu Suzuki
- Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | - Edward Cantu
- Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | - Jason D Christie
- Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.,Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
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21
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Inflammatory signalling associated with brain dead organ donation: from brain injury to brain stem death and posttransplant ischaemia reperfusion injury. J Transplant 2013; 2013:521369. [PMID: 23691272 PMCID: PMC3649190 DOI: 10.1155/2013/521369] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Revised: 01/19/2013] [Accepted: 01/22/2013] [Indexed: 01/26/2023] Open
Abstract
Brain death is associated with dramatic and serious pathophysiologic changes that adversely affect both the quantity and quality of organs available for transplant. To fully optimise the donor pool necessitates a more complete understanding of the underlying pathophysiology of organ dysfunction associated with transplantation. These injurious processes are initially triggered by catastrophic brain injury and are further enhanced during both brain death and graft transplantation. The activated inflammatory systems then contribute to graft dysfunction in the recipient. Inflammatory mediators drive this process in concert with the innate and adaptive immune systems. Activation of deleterious immunological pathways in organ grafts occurs, priming them for further inflammation after engraftment. Finally, posttransplantation ischaemia reperfusion injury leads to further generation of inflammatory mediators and consequent activation of the recipient's immune system. Ongoing research has identified key mediators that contribute to the inflammatory milieu inherent in brain dead organ donation. This has seen the development of novel therapies that directly target the inflammatory cascade.
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22
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Diamond JM, Porteous MK, Cantu E, Meyer NJ, Shah RJ, Lederer DJ, Kawut SM, Lee J, Bellamy SL, Palmer SM, Lama VN, Bhorade SM, Crespo M, Demissie E, Wille K, Orens J, Shah PD, Weinacker A, Weill D, Arcasoy S, Wilkes DS, Ware LB, Christie JD. Elevated plasma angiopoietin-2 levels and primary graft dysfunction after lung transplantation. PLoS One 2012; 7:e51932. [PMID: 23284823 PMCID: PMC3526525 DOI: 10.1371/journal.pone.0051932] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2012] [Accepted: 11/14/2012] [Indexed: 01/28/2023] Open
Abstract
INTRODUCTION Primary graft dysfunction (PGD) is a significant contributor to early morbidity and mortality after lung transplantation. Increased vascular permeability in the allograft has been identified as a possible mechanism leading to PGD. Angiopoietin-2 serves as a partial antagonist to the Tie-2 receptor and induces increased endothelial permeability. We hypothesized that elevated Ang2 levels would be associated with development of PGD. METHODS We performed a case-control study, nested within the multi-center Lung Transplant Outcomes Group cohort. Plasma angiopoietin-2 levels were measured pre-transplant and 6 and 24 hours post-reperfusion. The primary outcome was development of grade 3 PGD in the first 72 hours. The association of angiopoietin-2 plasma levels and PGD was evaluated using generalized estimating equations (GEE). RESULTS There were 40 PGD subjects and 79 non-PGD subjects included for analysis. Twenty-four PGD subjects (40%) and 47 non-PGD subjects (59%) received a transplant for the diagnosis of idiopathic pulmonary fibrosis (IPF). Among all subjects, GEE modeling identified a significant change in angiopoietin-2 level over time in cases compared to controls (p = 0.03). The association between change in angiopoietin-2 level over the perioperative time period was most significant in patients with a pre-operative diagnosis of IPF (p = 0.02); there was no statistically significant correlation between angiopoietin-2 plasma levels and the development of PGD in the subset of patients transplanted for chronic obstructive pulmonary disease (COPD) (p = 0.9). CONCLUSIONS Angiopoietin-2 levels were significantly associated with the development of PGD after lung transplantation. Further studies examining the regulation of endothelial cell permeability in the pathogenesis of PGD are indicated.
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Affiliation(s)
- Joshua M Diamond
- Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
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Yamamoto S, Okazaki M, Yamane M, Miyoshi K, Otani S, Kakishita T, Yoshida O, Waki N, Toyooka S, Oto T, Sano Y, Miyoshi S. Peculiar mechanisms of graft recovery through anti-inflammatory responses after rat lung transplantation from donation after cardiac death. Transpl Immunol 2012; 26:133-9. [DOI: 10.1016/j.trim.2011.11.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2011] [Revised: 10/03/2011] [Accepted: 11/04/2011] [Indexed: 11/25/2022]
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Bastarache JA, Diamond JM, Kawut SM, Lederer DJ, Ware LB, Christie JD. Postoperative estradiol levels associate with development of primary graft dysfunction in lung transplantation patients. ACTA ACUST UNITED AC 2012; 9:154-65. [PMID: 22361838 DOI: 10.1016/j.genm.2012.01.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2011] [Revised: 01/04/2012] [Accepted: 01/18/2012] [Indexed: 01/11/2023]
Abstract
BACKGROUND Primary graft dysfunction (PGD) frequently complicates lung transplantation in the immediate postoperative period. Both female gender and estradiol modulate the body's response to injury and can influence the rate of alveolar fluid clearance. OBJECTIVE We hypothesized that female gender and higher estradiol levels would be associated with a lower risk of PGD after lung transplantation. METHODS We measured plasma estradiol levels preoperatively, 6 hours postoperatively, and 24 hours postoperatively in a cohort of 111 lung transplant recipients at 2 institutions. RESULTS Mean age was 57 years (12.5) and 52% were female. Median postoperative estradiol level was 63.9 pg/mL (interquartile range, 28.8-154.3 pg/mL) in male and 65.1 pg/mL (interquartile range, 28.4-217.2 pg/mL) in female patients. Contrary to our hypothesis, higher estradiol levels at 24 hours were associated with an increased risk of PGD at 72 hours in male patients (P = 0.001). This association was preserved when accounting for other factors known to be associated with PGD. However, there was no relationship between gender and risk of PGD or between estradiol levels and PGD in females. CONCLUSION These findings suggest that there might be different biologic effects of estrogens in males and females, and highlight the importance of considering gender differences in future studies of PGD.
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Affiliation(s)
- Julie A Bastarache
- Division of Allergy, Pulmonary and Critical Care, Vanderbilt University School of Medicine, Nashville, TN 37232-2650, USA.
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25
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Endothelin-1 governs proliferation and migration of bronchoalveolar lavage-derived lung mesenchymal stem cells in bronchiolitis obliterans syndrome. Transplantation 2011; 92:155-62. [PMID: 21701423 DOI: 10.1097/tp.0b013e318222c9ea] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND Bronchiolitis obliterans syndrome (BOS) has an incidence of 57% at 5 years after lung transplantation, accounts for 30% of all deaths 3 years posttransplant and because treatment options are extremely limited, it constitutes a significant health care problem. Adult mesenchymal stem cells (MSCs) play a role in lung turnover; however, their role in BOS remains unknown. METHODS MSCs were isolated from bronchoalveolar lavage (BAL) in 101 lung allograft recipients. BAL was screened by protein array and MSCs were analyzed by real-time polymerase chain reaction, proliferation, migration, and enzyme linked immunosorbent assays. RESULTS Multipotent MSCs were isolated from BAL of lung recipients independent of BOS presence. However, MSCs from BOS patients proliferated at higher rates (P<0.001) and were associated with higher α-smooth muscle actin (P = 0.03) but lower surfactant protein B (P = 0.02) compared with those from no-BOS patients. Histological analysis revealed that MSCs are abundant in lung tissue of BOS patients. MSCs from BOS patients produced higher endothelin-1 (ET-1) amounts (P<0.001) compared with those from no-BOS; and ET-1 stimulated whereas ET-1 blockade suppressed MSC proliferation, migration, and differentiation. CONCLUSIONS These results indicate that MSCs are associated with BOS and are governed by ET-1. Targeting MSCs by ET-1 blockade might be useful in BOS treatment.
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Abstract
Primary graft dysfunction (PGD) is the most important cause of early morbidity and mortality following lung transplantation. PGD affects up to 25% of all lung transplant procedures and currently has no proven preventive therapy. Lung transplant recipients who recover from PGD may have impaired long-term function and an increased risk of bronchiolitis obliterans syndrome. This article aims to provide a state-of-the-art review of PGD epidemiology, outcomes, and risk factors, and to summarize current efforts at biomarker development and novel strategies for prevention and treatment.
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Affiliation(s)
- James C Lee
- Division of Pulmonary, Allergy and Critical Care Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
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Ropponen JO, Syrjälä SO, Krebs R, Nykänen A, Tikkanen JM, Lemström KB. Innate and adaptive immune responses in obliterative airway disease in rat tracheal allografts. J Heart Lung Transplant 2011; 30:707-16. [PMID: 21411341 DOI: 10.1016/j.healun.2010.12.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2010] [Revised: 12/08/2010] [Accepted: 12/29/2010] [Indexed: 10/18/2022] Open
Abstract
BACKGROUND We assessed cellular innate and adaptive immune responses in a rat heterotopic tracheal allograft model during the development of obliterative airway disease. METHODS Syngeneic tracheal grafts were transplanted heterotopically from DA to DA rats and fully MHC-mismatched allografts from DA to WF rats. The recipients received either no immunosuppression or two different doses of cyclosporine and were euthanized at 3, 10 and 30 days. Non-transplanted DA tracheas served as controls. Histologic, immunohistochemical and real-time RT-PCR analyses were performed. RESULTS The syngrafts had normal epithelium at 10 days and no tracheal occlusion was seen at 30 days. In non-immunosuppressed allografts, almost total loss of epithelium was observed at 10 days, culminating in tracheal occlusion at 30 days. The activation of innate immune response was observed during the ischemic period at 3 days in both groups. Influx of the infiltrating inflammatory cells was more prominent in the allografts. In syngrafts, mRNA expression of pro-inflammatory, but also tolerogenic, cytokines was significantly upregulated, whereas Th1 and Th17 priming factors were significantly downregulated. In allografts, prominent mRNA expression of pro-inflammatory cytokines was seen and adaptive Th1 and Th17 alloresponses were increased. Cyclosporine treatment reduced tracheal occlusion and inhibited both tolerogenic and pro-inflammatory T-cell responses in allografts. CONCLUSIONS Ischemia induced a self-limiting, alloantigen-independent innate immune response in syngrafts. In allografts, the predominant pro-inflammatory milieu and alloantigen-dependent Th1 and Th17 responses were linked to the development of obliterative airway disease and were inhibited by cyclosporine treatment.
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Affiliation(s)
- Jussi O Ropponen
- Cardiopulmonary Research Group, Transplantation Laboratory, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
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The contribution of airway and lung tissue ischemia to primary graft dysfunction. Curr Opin Organ Transplant 2011; 15:552-7. [PMID: 20693898 DOI: 10.1097/mot.0b013e32833e1415] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
PURPOSE OF REVIEW Primary graft dysfunction (PGD) is the primary obstacle to short-term survival for post-lung transplant patients. PGD is a form of acute lung injury secondary to donor brain death and ischemia-reperfusion damage to the allograft affecting 10-25% of all lung transplant recipients. This article reviews the significant role of allograft ischemia in the phenotypic presentation of PGD and the evidence for activation and disruption of normal cellular pathways for the development and long-term sequelae. RECENT FINDINGS Pathways implicated in the pathogenesis of PGD resultant from tissue ischemia include abnormalities in coagulation and fibrinolysis, epithelial cell injury, endothelial cell dysfunction, chemotaxis, and alterations in cell adhesion. Blood and bronchoalveolar lavage fluid biomarkers from these pathways have been increasingly identified as useful for diagnosing and predicting the development of severe PGD. SUMMARY Future efforts at preventing and treating severe PGD should focus on techniques for altering the pathways involved in PGD pathogenesis. Ex-vivo lung perfusion and transduction with interleukin-10 are promising modalities for preventing PGD and expanding the available lung transplant donor pool.
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Salama M, Jaksch P, Andrukhova O, Taghavi S, Klepetko W, Aharinejad S. Endothelin-1 is a useful biomarker for early detection of bronchiolitis obliterans in lung transplant recipients. J Thorac Cardiovasc Surg 2010; 140:1422-7. [PMID: 21078427 DOI: 10.1016/j.jtcvs.2010.08.046] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2010] [Revised: 08/03/2010] [Accepted: 08/15/2010] [Indexed: 10/18/2022]
Abstract
OBJECTIVES Bronchiolitis obliterans (BO) is a severe complication limiting long-term survival after lung transplantation. To date, no cure exists for BO, and the mechanisms leading to BO are not well understood. Endothelin-1 (ET-1) is a potent mitogenic and profibrotic peptide produced by pulmonary vascular endothelial cells that play a role in the pathophysiology of lung allograft dysfunction. Whether ET-1 could predict BO syndrome (BOS) development is unknown. METHODS Transbronchial biopsy specimens and serum and bronchoalveolar lavage were obtained from 30 lung transplantation patients with and 30 without BOS at 3 points. The serum and bronchoalveolar lavage ET-1 concentrations were measured by enzyme-linked immunosorbent assay, and the ET-1 mRNA expression in the transbronchial biopsy specimens was examined using real-time polymerase chain reaction. RESULTS The pretransplant ET-1 serum concentrations were greater in the patients with BOS (P = .02); and ET-1 mRNA was significantly upregulated in the lung grafts of those with versus those without BOS at 3 and 12 months after transplant (P = .01). At 3 and 12 months after transplantation, the ET-1 concentrations were significantly elevated in the serum (P < .01 and P < .0001, respectively) and bronchoalveolar lavage (P < .01 and P = .02, respectively) of patients with compared with those without BOS. On logistic regression analysis, the pretransplant and 3-month post-transplant serum ET-1 level predicted for BOS (odds ratio, 1.01; 95% confidence interval, 1.004-1.025; P < .007; odds ratio, 2.9; 95% confidence interval, 1.01-8.52; P < .001). The serum ET-1 level at 12 months was diagnostic for BOS (odds ratio, 3.9; 95% confidence interval, 1.42-10.80; P = .008). CONCLUSIONS Elevated serum ET-1 concentrations were predictive of BOS, and the assessment of circulating ET-1 might be beneficial in diagnosing and monitoring BO.
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Affiliation(s)
- Mohamed Salama
- Department of Cardiothoracic Surgery, Medical University of Vienna, Vienna, Austria
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Hagedorn PH, Burton CM, Sahar E, Domany E, Cohen IR, Flyvbjerg H, Iversen M. Integrative analysis correlates donor transcripts to recipient autoantibodies in primary graft dysfunction after lung transplantation. Immunology 2010; 132:394-400. [PMID: 21070236 DOI: 10.1111/j.1365-2567.2010.03373.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Up to one in four lung-transplanted patients develop pulmonary infiltrates and impaired oxygenation within the first days after lung transplantation. Known as primary graft dysfunction (PGD), this condition increases mortality significantly. Complex interactions between donor lung and recipient immune system are the suspected cause. We took an integrative, systems-level approach by first exploring whether the recipient's immune response to PGD includes the development of long-lasting autoreactivity. We next explored whether proteins displaying such differential autoreactivity also display differential gene expression in donor lungs that later develop PGD compared with those that did not. We evaluated 39 patients from whom autoantibody profiles were already available for PGD based on chest radiographs and oxygenation data. An additional nine patients were evaluated for PGD based on their medical records and set aside for validation. From two recent donor lung gene expression studies, we reanalysed and paired gene profiles with autoantibody profiles. Primary graft dysfunction can be distinguished by a profile of differentially reactive autoantibodies binding to 17 proteins. Functional analysis showed that 12 of these proteins are part of a protein-protein interaction network (P=3 x 10⁻⁶) involved in proliferative processes. A nearest centroid classifier assigned correct PGD grades to eight out of the nine patients in the validation cohort (P=0·048). We observed significant positive correlation (r=0·63, P=0·011) between differences in IgM reactivity and differences in gene expression levels. This connection between donor lung gene expression and long-lasting recipient IgM autoantibodies towards a specific set of proteins suggests a mechanism for the development of autoimmunity in PGD.
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Affiliation(s)
- Peter H Hagedorn
- Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet, Building 208, DK-2800 Lyngby, Denmark.
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