ABSTRACT
BACKGROUND: The association between interleukin-1ß (IL-1ß) concentrations during ex vivo lung perfusion (EVLP) with donor organ quality and post-lung transplant outcome has been demonstrated in several studies. The mechanism underlying IL-1ß-mediated donor lung injury was investigated using a paired single-lung EVLP model. METHODS: Human lung pairs were dissected into individual lungs and perfused on identical separate EVLP circuits, with one lung from each pair receiving a bolus of IL-1ß. Fluorescently labeled human neutrophils isolated from a healthy volunteer were infused into both circuits and quantified in perfusate at regular timepoints. Perfusates and tissues were subsequently analyzed, with perfusates also used in functional assays. RESULTS: Neutrophil numbers were significantly lower in perfusate samples collected from the IL-1ß-stimulated lungs consistent with increased neutrophil adhesion ( P = 0.042). Stimulated lungs gained significantly more weight than controls ( P = 0.046), which correlated with soluble intercellular adhesion molecule-1 (R 2 = 0.71, P = 0.0043) and von-Willebrand factor (R 2 = 0.39, P = 0.040) in perfusate. RNA expression patterns for inflammatory genes were differentially regulated via IL-1ß. Blockade of IL-1ß significantly reduced neutrophil adhesion in vitro ( P = 0.025). CONCLUSION: These data illustrate the proinflammatory functions of IL-1ß in the context of EVLP, suggesting this pathway may be susceptible to therapeutic modulation before transplantation.
Subject(s)
Lung Transplantation , Humans , Perfusion/adverse effects , Interleukin-1beta/pharmacology , Interleukin-1beta/metabolism , Lung Transplantation/adverse effects , Lung/metabolism , InflammationABSTRACT
Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)1, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination2,3. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials.
Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Receptors, Virus , Ursodeoxycholic Acid , Animals , Humans , Mice , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , COVID-19/prevention & control , Receptors, Virus/genetics , Receptors, Virus/metabolism , Retrospective Studies , SARS-CoV-2/metabolism , COVID-19 Drug Treatment , Cricetinae , Transcription, Genetic , Ursodeoxycholic Acid/pharmacology , Lung/drug effects , Lung/metabolism , Organoids/drug effects , Organoids/metabolism , Liver/drug effects , Liver/metabolism , Nasal Mucosa/drug effects , Nasal Mucosa/metabolism , Registries , Reproducibility of Results , Liver TransplantationABSTRACT
PURPOSE OF REVIEW: Lung transplantation offers the only realistic therapeutic option for patients with end-stage lung disease. However, this is impacted by a shortfall in availability of suitable donor-lungs. Normothermic machine perfusion of donor-lungs outside the donor body also known as ex-vivo lung perfusion (EVLP) offers a potential solution through objective assessment, reconditioning and treatment of donor-lungs initially deemed unsuitable for use. This review discusses key advances and challenges in the wider clinical adoption of this technology. RECENT FINDINGS: This review will summarize key research within the following areas: recent clinical trials utilizing EVLP, logistical challenges, EVLP protocol innovations, novel assessment methods and current research into therapeutic modulation of lung function during EVLP. SUMMARY: Normothermic machine perfusion of donor-lungs ex-vivo offers a promising platform to assess and modulate donor-lung quality prior to transplantation. Consensus on how and when to best utilize EVLP is yet to be reached, meaning that widespread clinical adoption of the technology has not yet become a reality. Further work is needed on agreed indications, perfusion protocols and organization of services before becoming a regularly used procedure prior to lung transplantation.
