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Towards a Detailed Understanding of the Red Blood Cell Storage Lesion

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Towards a Detailed Understanding of the Red Blood Cell Storage Lesion TOWARDS A DETAILED UNDERSTANDING OF THE RED BLOOD CELL STORAGE LESION and its consequences for in vivo survival following transfusion ANDREAS HULT Department of Community Medicine and Rehabilitation Department of Surgical and Perioperative Sciences Department of Integrative Medical Biology Umeå 2015 Responsible publisher under swedish law: the Dean of the Medical Faculty This work is protected by the Swedish Copyright Legislation (Act 1960:729) ISBN: 978-91-7601-288-8 ISSN: 0346-6612 Cover illustration by MD, PhD Gustav Andersson. Copyright with artist. Elektronisk version tillgänglig på http://umu.diva-portal.org/ Printed by: Print & Media Umeå, Sweden 2015 Till Simon och Elvira i ii Table of Contents Table of Contents .......................................................................... iii Abstract ......................................................................................... v Abbreviations ............................................................................... vii Enkel sammanfattning på svenska .................................................ix List of original papers .................................................................. xiii Introduction ................................................................................... 1 The leukocytes .................................................................................... 1 Innate immunity ................................................................................................. 2 Pattern recognition receptors (PRRs) ................................................................ 3 Adaptive immunity ............................................................................................. 4 Tolerance vs. Immunity ...................................................................................... 5 The Red blood cell ............................................................................... 5 Function ............................................................................................................. 5 Erythropoiesis .................................................................................................... 7 The life and death of RBCs ................................................................................. 8 Eryptosis ............................................................................................................. 9 Recognition and phagocytosis of RBCs .............................................................. 9 Immune cells of the spleen .............................................................................. 11 RBC transfusion .................................................................................13 History .............................................................................................................. 13 Demographics .................................................................................................. 14 Effects of RBC transfusion ................................................................................ 14 RBC storage conditions .................................................................................... 15 The storage lesion ............................................................................................ 15 Risks associated with transfusion .................................................................... 17 How to study RBCs .............................................................................18 Human studies ................................................................................................. 18 Animal models ................................................................................................. 18 Aims ............................................................................................ 20 Materials and methods ................................................................ 21 Human studies (paper 1) ....................................................................21 Donation and reinfusion .................................................................................. 21 Blood analysis ................................................................................................... 21 Maximal aerobic capacity (VO2max) assessment ............................................. 22 Animal studies (paper 2 and 3) ...........................................................22 Labeling of RBCs ............................................................................................... 22 The mouse model for RBC storage and transfusion ......................................... 23 In vitro characteristics of stored RBCs ............................................................. 24 In vitro phagocytosis ........................................................................................ 24 Ethics ................................................................................................................ 25 iii Statistical analysis ............................................................................................ 25 Results ......................................................................................... 26 Paper 1 ..............................................................................................26 Transfusion of cryopreserved RBCs leads to acute accelerated RBC breakdown ......................................................................................................................... 26 Absent pro-inflammatory response in the acute phase after transfusion ....... 26 Additional results ............................................................................................. 27 Paper 2 ..............................................................................................28 Stored human RBCs contain a subset of Ca2+-high cells ................................... 28 Characteristics of eryptotic murine RBCs ......................................................... 28 In vivo uptake of Ca2+-RBCs is located to the splenic marginal zone in a CD47- independent manner ....................................................................................... 28 Additional results ............................................................................................. 29 Paper 3 ..............................................................................................30 Characteristics of the murine model for storage and transfusion ................... 30 Phagocytosis of stored human and mouse RBCs is serum dependent and mediated by scavenger receptors .................................................................... 30 Additional results ............................................................................................. 31 Discrimination of RBC age fractions by in vivo biotinylation ....................... 31 Role of the RBC age at the start of storage for their 24 h survival post transfusion ................................................................................................... 32 Phthalates during storage ............................................................................ 32 CD47 on stored murine RBCs does not influence the rapid elimination that occurs during the first 24 h .......................................................................... 33 Discussion .................................................................................... 33 Frozen vs. liquid stored RBCs ........................................................................... 34 Inflammation after transfusion? ...................................................................... 34 The mouse model for storage and transfusion ................................................ 35 The role of calcium uptake in the storage lesion ............................................. 36 Impact of storage on RBCs - Senescence, eryptosis, or both? ......................... 37 How are stored RBCs presented to the immune system upon transfusion? ... 38 CD47 in senescence, eryptosis and the storage lesion .................................... 39 Scavenger receptor mediated phagocytosis of stored RBCs ............................ 39 The role of serum in phagocytosis of stored cells ............................................ 40 Concluding remarks ......................................................................................... 41 Conclusions .................................................................................. 41 Acknowledgements ..................................................................... 43 References ................................................................................... 46 iv Abstract Red blood cells (RBCs) are vital for oxygen delivery to tissues and constitute the vast majority of all cells in blood. After leaving the red bone marrow as mature cells, RBCs have a lifespan of approximately 120 days before they are removed from the circulation by macrophages, mainly in the spleen and liver. RBC transfusion is a common therapy in modern healthcare. Major surgery, numerous cancer treatments and other, often lifesaving, interventions would be unthinkable without available blood supply. For this reason, hospitals store donated RBCs in blood banks. The metabolic and structural changes that occur during prolonged storage of RBCs (the storage lesion) have been studied in detail in vitro and include oxidative stress, a reduction in glycolysis, increased membrane rigidity and shedding of microparticles from the RBC membrane. Stored RBCs share several features of senescent
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