Endothelin receptor antagonist improves donor lung function in an ex vivo perfusion system

Kafa Walweel ,J Reid,L James,Kavita Bisht ,Sara Diab ,Nchafatso G Obonyo ,Jacky Y Suen ,Sanne Pedersen ,Sebastiano Maria Colombo ,K Skeggs,Louise E See Hoe ,Ps Macdonald ,Leticia Pretti Pimenta ,Margaret Passmore ,David C Mcgiffin ,Mahè Bouquet ,D Platts ,Ai-Ching Boon ,Matthew A Wells ,Kieran Hyslop ,A K Stevenson,Liam E Marshall ,Emily S Wood ,Debra Black ,Nicole Bartnikowski ,Durai Prabhu ,John F Fraser

doi:10.1186/s12929-020-00690-7

Abstract

BackgroundA lung transplant is the last resort treatment for many patients with advanced lung disease. The majority of donated lungs come from donors following brain death (BD). The endothelin axis is upregulated in the blood and lung of the donor after BD resulting in systemic inflammation, lung damage and poor lung graft outcomes in the recipient. Tezosentan (endothelin receptor blocker) improves the pulmonary haemodynamic profile; however, it induces adverse effects on other organs at high doses. Application of ex vivo lung perfusion (EVLP) allows the development of organ-specific hormone resuscitation, to maximise and optimise the donor pool. Therefore, we investigate whether the combination of EVLP and tezosentan administration could improve the quality of donor lungs in a clinically relevant 6-h ovine model of brain stem death (BSD).MethodsAfter 6 h of BSD, lungs obtained from 12 sheep were divided into two groups, control and tezosentan-treated group, and cannulated for EVLP. The lungs were monitored for 6 h and lung perfusate and tissue samples were processed and analysed. Blood gas variables were measured in perfusate samples as well as total proteins and pro-inflammatory biomarkers, IL-6 and IL-8. Lung tissues were collected at the end of EVLP experiments for histology analysis and wet-dry weight ratio (a measure of oedema).ResultsOur results showed a significant improvement in gas exchange [elevated partial pressure of oxygen (P = 0.02) and reduced partial pressure of carbon dioxide (P = 0.03)] in tezosentan-treated lungs compared to controls. However, the lungs hematoxylin–eosin staining histology results showed minimum lung injuries and there was no difference between both control and tezosentan-treated lungs. Similarly, IL-6 and IL-8 levels in lung perfusate showed no difference between control and tezosentan-treated lungs throughout the EVLP. Histological and tissue analysis showed a non-significant reduction in wet/dry weight ratio in tezosentan-treated lung tissues (P = 0.09) when compared to control.ConclusionsThese data indicate that administration of tezosentan could improve pulmonary gas exchange during EVLP.

Highlights

Lung transplantation is the ultimate solution for patients with end stage respiratory failure; its success is limited by significant donor organ shortages [1,2,3,4,5,6]
We found that tezosentan administration resulted in improved pulmonary gas exchange post brain stem death (BSD) with improved oxygenation in the lungs during ex vivo lung perfusion (EVLP)
Lung function during EVLP Pulmonary gas exchange was significantly better throughout EVLP in tezosentan-treated group than in control group (Fig. 2)

Summary

Methods

After 6 h of BSD, lungs obtained from 12 sheep were divided into two groups, control and tezosentantreated group, and cannulated for EVLP. The lungs were monitored for 6 h and lung perfusate and tissue samples were processed and analysed. Blood gas variables were measured in perfusate samples as well as total proteins and pro-inflammatory biomarkers, IL-6 and IL-8. Lung tissues were collected at the end of EVLP experiments for histology analysis and wet-dry weight ratio (a measure of oedema)

Results

Introduction

Methodology

Discussion

Conclusion