Assessment of donor lung injury following brain death. A clinical and experimental study.
Beoordeling van longschade in de donor na hersendood. Een klinische en experimentele studie.
Wauters, Shana; S0198011;
Lung transplantation (LTx) is an effective treatment modality for selected patients suffering from any form of end-stage pulmonary disease. However, this life-saving treatment is still hampered by the scarcity of suitable donor lungs and the development of primary graft dysfunction (PGD) and chronic rejection after transplantation. At present, donation after brain death (BD) continues to be the major donor source for LTx. But it is known for many years that the process of brain death may have detrimental effects on the functional performance of all potential donor organs and the lung in particular. Better insights into this BD related-donor lung injury can contribute to a better donor management protocol and ultimately lead to an increase of lung donors suitable for transplantation.By reviewing medical charts of brain death donors, we showed that donor cause of brain death as well as the length of the interval from brain injury to brain death does not impact survival and freedom from BOS after LTx. In addition, recipients from BD donors with an interval longer than 10 hours prior to lung preservation had a superior survival unrelated to BOS, which may well be the result of a longer and better donor management. In a second clinical study, a candidate gene association study of LTx recipients from BD donors revealed a significant association between polymorphisms in TLR4 and PGD after LTx, suggesting that innate immune activation may be linked to the development of PGD after LTx. Since the pathogenesis of BD-related donor lung injury is still poorly understood, a good animal model is indispensable to further investigate this matter. Most experimental models for the research towards BD-induced organ injury use large animals, but these models are limited for immunological analyses. Therefore, a mouse model of BD was developed because it offers opportunities for immunological assays and genetic variance. BD in the mouse using the balloon inflation technique was confirmed by small animal positron emission tomography. After confirmation, this model was further developed and BD was investigated at different time points after induction. Six hours of BD revealed an increase in total cells in broncho-alveolar lavage fluid (BALF) and increased percentage of neutrophils and lymphocytes. Increased levels of the inflammatory cytokine, IL-6, were seen and lung injury (congestion, hemorrhage and neutrophils) was more pronounced after 3h and 6h. However, differences between sham- and BD-operated animals were limited. Further optimization of the model will give us opportunities for further mechanistic studies guiding future prevention and possible treatment strategies to counteract BD-related lung injury.
Table of Contents:
TABLE OF CONTENTS
List of abbreviations 11
Chapter I: GENERAL INTRODUCTION 13
Chapter II: RATIONALE AND AIMS 29
Chapter III: CLINICAL STUDIES 33
III-A. Donor cause of brain death and related time intervals 35
III-B. Toll-like receptor 4 polymorphisms and the risk of primary graft dysfunction after lung transplantation 59
Chapter IV: EXPERIMENTAL STUDIES 71
IV-A. FDG-µPET confirms brain death in a murine model to study donor lung injury 73
IV-B. Developing a murine brain death model to evaluate lung injury 87
IV-C. Evaluating lung injury at different time points following brain death 107
Chapter V: GENERAL DISCUSSION AND FUTURE PERSPECTIVES 125
Curriculum Vitae 145
List of publications 147