Concomitant Endothelin‐1 Overexpression in Lung Transplant Donors and Recipients Predicts Primary Graft Dysfunction

Abstract

Primary graft dysfunction (PGD) causes significant morbidity following lung transplantation (LTX).Mortality is high in PGD and therapeutic strategies are limited. To investigate whether endothelin-1 (ET-1) that mediates increased vascular permeability and edema formation in lung grafts can predict PGD, ET-1 mRNA expression was examined in lung tissue biopsies of 105 donors and recipients obtained shortly before LTX. Serum ET-1 concentration was assessed by ELISA. PGD grade was diagnosed and scored by oxygenation and radiological characteristics according to ISHLT guidelines. PGD grade 3 developed in 11% of patients. ET-1 mRNA expression was significantly increased in both donor (p < 0.0001) and recipient (p = 0.01) developing PGD as compared to no PGD group. Pretransplant ET-1 serum concentrations were elevated in recipients with PGD as compared to no PGD group (p < 0.0001), although serum ET-1 was not different between donors whose grafts developed PGD grades 0-3. In regression analysis, concomitant elevated donor tissue ET-1 and recipient serum ET-1 predicted PGD grade 3. This study indicates that pretransplant ET-1 mRNA overexpression in donors associated with elevated pretransplant serum ET-1 in recipients contribute to PGD development and that their assessment might be beneficial to predict PGD and to identify recipients who could benefit from a targeted ET-1 blockade.

The role of the endothelin-1 pathway as a biomarker for donor lung assessment in clinical ex vivo lung perfusion

“…10,11 Furthermore, in clinical lung transplantation, ET-1 messenger RNA (mRNA) levels in lung tissue biopsy specimens taken immediately before reperfusion have been shown to correlate with severe PGD. 8 In the setting of EVLP, the ET-1 axis would be of particular interest because, unlike most mediators that tend to accumulate in the absence of hepatic or renal clearance mechanisms in the ex vivo circuit, ET-1 is mainly metabolized by the lung. 12 We hypothesized that in metabolically active high-risk donor lungs perfused with a clinical intent, the ET-1 axis is active and reflects graft performance during EVLP and after transplantation.…”

Update on lung transplantation: programmes, patients and prospects

“…Similarly, the level of long pentraxin 3 (a TLR agonist implicated in reperfusion injury) and endothelin-1 expression in both donors and recipients predicts PGD [374,375]. Other researchers, noting the complexity of injury and the diversity of material released from damaged cell and tissue responses to injury, have focused on gene transcript patterns or clusters of protein biomarkers [376].…”

The implications of brain death in donor lung injury: investigation and blockade of the endothelin axis

“…Data is accumulating of the role of ET-1 in brain death and organ donation; activation of the endothelin axis has been demonstrated early in BD related pulmonary inflammation, [88] it contributes to complications associated with human lung donation, [212,340,341] and it may contribute to the altered cardiopulmonary haemodynamics observed in the current study. As a potent mitogen, ET-1 stimulates smooth muscle hyperplasia and leads to airway remodelling and oedema.…”

“…[88,211] Salama et al demonstrated a correlation between donor ET-1 and primary graft dysfunction (PGD). [212] In this study,…”

“…Upregulation of endothelin receptors "primes" the lungs for post-transplant injury, [24] and may partly explain the relationship between endothelin expression and primary graft dysfunction that has been observed in human lung allograft recipients. [212] Haemodynamic instability has limited the duration of previous BD animal studies and supportive measures used to extend these models to clinically relevant timeframes are difficult to apply to small animals. [186,210,306] …”