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

Abstract

Background: A 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).

Methods: After 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).

Results: Our 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.

Conclusions: These data indicate that administration of tezosentan could improve pulmonary gas exchange during EVLP.

Keywords: Brain stem death; EVLP; Endothelin axis; Lung transplantation; Tezosentan.

Fig. 1

Schematic diagram of an EVLP circuit (Vivoline LS1 system, Vivoline Medical AB, Lund, Sweden). HCU heater cooler unit, LA left atrium, PA pulmonary artery [55]

Fig. 2

Gas exchange variables in BSD lungs treated with tezosentan compared to controls during EVLP. The oxygenation capacity (ΔpO₂, a) was calculated as the difference in the partial pressure of O₂ between the oxygenator (venous blood) and LA during evaluation phase. ΔpCO₂ (b) was calculated as the difference in CO₂ partial pressure in LA before and after EVLP. Data is expressed as mean ± SEM. *P < 0.05 versus control

Fig. 3

Indices of lung oedema. Lung wet-to-dry weight ratio (a) and total protein concentration (b) in tezosentan-treated lungs perfusate compared to controls. Wet-to-dry weight ratios were measured at the end of EVLP, whereas, total protein in perfusate samples were measured throughout the EVLP. Data is expressed as mean ± SEM

Fig. 4

IL-6 (a) and IL-8 (b) levels in lung perfusate treated with tezosentan compared to controls during EVLP. Data is expressed as mean ± SEM

Fig. 5

Microscopic BSD lung injuries before and after EVLP. Representative haematoxylin–eosin tissue sections of lungs before (Pre-EVLP) and after 12 h of reperfusion in presence and absence of tezosentan (Post-EVLP and Post-EVLP + TEZ). Representative sections are shown at ×40 magnification. TEZ tezosentan