Angiotensin-(1-7) preconditioning during 10°C static preservation improves early post-transplant graft function in a rat lung transplantation model.

BACKGROUND

Ischemia-reperfusion injury (IRI) plays an important role in early graft failure after lung transplantation. We hypothesized that treating injured donor lungs with angiotensin-(1-7) [Ang-(1-7)], a biologically active product of the protective axis of the renin-angiotensin system, during 10°C preservation reduces IRI and improves lung transplant outcomes.

METHODS

In Lewis rats, aspiration injury was induced through intratracheal instillation of hydrochloric acid (0.1N). Acid-injured donor lungs (n = 5/group) were randomized to lungs flushed with low-potassium dextran-glucose solution (LPDG; Control) or LPDG plus Ang-(1-7) and stored for 12 hours at 10ºC. A third group included immediate transplantation (MinCIT). Left lungs were transplanted and reperfused for 2 hours.

RESULTS

After transplantation, lungs preconditioned with Ang-(1-7) showed significantly better oxygenation (p = 0.004) and lower interleukin-8 levels (p = 0.01) compared to other groups. Results of a panel of mitochondrial biogenesis markers showed higher fold regulations for mitofusin 2 (p = 0.03), when lungs were flushed with Ang-(1-7) relative to Control. The improvement in lung function was dependent on Mas receptor activation and specific to 10°C preservation.

CONCLUSIONS

We demonstrate that the enrichment of lung preservation flush solution with Ang-(1-7) results in superior post-transplant graft function, amplifying the beneficial effects of hypothermic preservation on injured lungs. The maintenance of mitochondrial and cellular health through preconditioning with Ang-(1-7) may result in better clinical outcomes.