Novel diagnostics and treatment of acute lung injury and transplantation - Preclinical and clinical implementation

Abstract: Acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS) limit the utilization of donor lungs for transplantation but is also a common cause of death in the intensive care unit. There is a general lack of diagnostic tools by which to assess lung function in ARDS but, in addition, the treatments offered are limited. In the present thesis, the aim was to explored particles in exhaled air as a diagnostic tool for ALI, but also the use of cytokines as a treatment target for such injury. A porcine model was used where ALI and ARDS were induced, using either lipopolysaccharide (LPS), repeated lavage or gastric content aspiration. The lungs were evaluated in vivo during non-transplant and transplant conditions and with or without extra corporal membrane oxygenation (ECMO) support. The lungs were also evaluated by machine perfusion using ex vivo lung perfusion (EVLP). Measurements of exhaled breath particles (EBP), expressed as particle flow rate (PFR), from the airways preceded early signs of ARDS, not only in an LPS-induced ARDS porcine model but could also be used for monitoring lung injury during ECMO treatment both in pigs but also in patients with COVID-19-induced ARDS. Increased PFR also preceded clinical signs of ALI in the gastric aspiration model, whereas only a trend could be seen in the repeated lavage model. The LPS models showed a similar pattern of massive cytokine release as also seen in the COVID-19 patients. The cytokines were detected both in plasma and in bronchoalveolar lavage fluid (BALF). The cytokine release was not as prominent in the repeated lavage model and in the gastric aspiration model. In the collected samples of EBPs, specific proteins connected to ALI were detected in all animal models. Given the role of cytokines in lung injury, cytokines are interesting targets for lung repair and regeneration. EVLP has lately gained acceptance as an evaluation platform for marginal lungs initially declined for transplantation. A new aspect is using the platform to repair or restore lung function of donor lungs with ALI that are declined both for EVLP and for transplantation. A cytokine filter was connected to the EVLP during perfusion of LPS-damaged donor lungs. The cytokine filter restored lung function after 4 hours of EVLP, shown by improved oxygenation and confirmation by histology. For optimal treatment, the restored lungs were transplanted into a healthy recipient and received another 12 hours of cytokine filtration post-transplantation. The lungs were evaluated regarding the development of primary graft dysfunction (PGD) where cytokines seem to be an important target given the outcome of significantly less PGD in the group receiving cytokine filtration. In conclusion, PFR may be used as a diagnostic tool in mechanical ventilation and to detect ALI, but also to monitor lung injury over time. Cytokines as a treatment target have their role in restoring lung function in damaged donor lungs.