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Upregulation of the endothelin axis in alveolar macrophages following brain stem death in a murine model

Introduction

Outcomes post lung transplantation continue to improve, but early pulmonary dysfunction dictates long-term morbidity and mortality. Ischaemia reperfusion injury is a precipitant of poor postoperative outcome in lung transplantation and may cause primary graft dysfunction (PGD). A number of processes are thought to contribute to PGD. Relatively little is understood of the role of brain stem death (BSD) in subsequent organ dysfunction. We wished to examine the effect of BSD on the endothelin (ET) axis.

Methods

Following ethics approval, 14 Wistar–Kyoto rats were anaesthetised, with tracheostomy and arterial and venous cannulation. A 200 μl Fogarty's balloon catheter was inserted via a burr hole into the subdural vault. The balloon was inflated in the experimental group but not the control group. Four hours of positive pressure ventilation were followed by euthanasia and organ retrieval. Lung tissue was stained for H&E for morphology, and alveolar macrophages (AM) were identified by anti-CD68 staining. AM were stained with a monoclonal anti-ET-1 antibody, as well as the polyclonal anti-ET-A and ET-B.

Results

All animals survived the experiment. There was a significant increase in the ratio of AM to neutrophils (P = 0.002). The ET-1 content on the AM was significantly increased in the experimental group (27.57 ± 5.26 vs 7.01 ± 1.75, P < 0.0001).

Conclusion

In this model, BSD was associated with an increase in the ratio of AM to neutrophils, and there was significant upregulation of the endothelin axis on these AM, as evidenced by raised levels of ET-1, ET-A and ET-B. There may be a role for endothelin blockade in the BSD organ donor. This may increase the yield of organs that can be accepted for transplantation and improve early graft function in the recipient.

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Fraser, J., Sutherland, A., Kermeen, F. et al. Upregulation of the endothelin axis in alveolar macrophages following brain stem death in a murine model. Crit Care 11, P473 (2007). https://0-doi-org.brum.beds.ac.uk/10.1186/cc5633

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Keywords

  • Alveolar Macrophage
  • Lung Transplantation
  • Ischaemia Reperfusion Injury
  • Ischaemia Reperfusion
  • Positive Pressure Ventilation