Biology subjects

Ferdinand, J. R.

Publications and source records attributed to Ferdinand, J. R..

2 recordsLinked to original sources

bioRxiv2019

Transcriptional analysis identifies novel biomarkers associated with successful ex-vivo perfusion of human donor lungs

Transplantation is an effective treatment for end-stage lung disease but donor organ shortage is a major problem. Ex-vivo lung perfusion (EVLP) of marginal organs enables functional assessment under normothermic conditions to facilitate clinical decision-making around utilisation, but the molecular processes occurring during EVLP, and how they differ between more or less viable lungs, remains to be determined. Here we used RNA sequencing to delineate changes in gene expression occurring in n=10 donor lungs undergoing EVLP, comparing lungs that were deemed transplantable (n=6) to those deemed unusable (n=4). We found that lungs deemed suitable for transplantation following EVLP had reduced induction of a number of innate immune pathways during EVLP, but a greater increase in genes involved in oxidative phosphorylation, a critical ATP-degenerating pathway. Furthermore, SCGB1A1, a gene encoding an anti-inflammatory secretoglobin CC10, and other club cell genes were significantly increased in transplantable lungs following perfusion, whilst CHIT-1 was decreased. Using a larger validation cohort (n=18), we confirmed that the ratio of CHIT1 and SCGB1A1 protein levels in lung perfusate have potential utility to distinguish transplantable and non-transplantable lungs (AUC 0.81). Together, our data identify novel biomarkers that may assist with pre-transplant lung assessment, as well as pathways that may amenable to therapeutic intervention during EVLP.\n\nSingle sentence summaryTranscriptional changes in lungs undergoing ex vivo normothermic perfusion identify chitinase1 and club cell genes as potential biomarkers to guide utilisation

physiology↗

bioRxiv2019

Investigation of the transcriptional profile of human kidneys during machine perfusion reveals potential benefits of haemoadsorption

Transplantation is the optimal treatment for most patients with end stage kidney disease but organ shortage is a major challenge. Normothermic machine perfusion (NMP) has been used to re-condition marginal organs but the mechanisms by which NMP might benefit transplant kidneys are not fully understood. Furthermore, the question of whether removal of pro-inflammatory mediators from the perfusate might offer additional benefits in optimising kidneys prior to transplantation has not been addressed. Using pairs of human kidneys obtained from the same donor, we compared the effect of NMP with that of cold storage on the global transcriptome of kidneys, and then went on to investigate the impact of adding a haemoadsorption device to the NMP circuit. We found that cold storage significantly reduced the expression of inflammatory genes, but also of genes required for energy generation such as those encoding oxidative phosphorylation (OXPHOS) enzymes. In contrast, during NMP, there was marked upregulation OXPHOS genes, as well as a number of immune and inflammatory pathway genes. The induction of inflammatory genes during NMP was substantially attenuated by the addition of a haemoadsorber to the perfusion circuit, which also further increased OXPHOS pathway gene expression. Together, our data suggest that absorption of pro-inflammatory mediators from the perfusate represents a useful intervention that may further improve organ viability and should be tested in clinical practice.\n\nSingle sentence summary: The use of a haemoadsorber during machine perfusion reduces inflammatory gene expression, with potential benefits for kidney transplantation.

physiology↗