Original pre-clinical scienceEndothelial protection in lung grafts through heparanase inhibition during ex vivo lung perfusion in rats
Section snippets
Clinical EVLP and lung transplantation
All procedures were performed under the approval of the Institutional Review Board at the University of Pittsburgh. Clinical EVLP was performed with XPS machine and STEEN solution (XVIVO Perfusion AB, Denver, CO) for lung grafts with marginal quality from death donors. The criteria for marginal quality lungs and the details regarding EVLP methodology followed those applied for a clinical trial (NOVEL Lung Trial; ClinicalTrials.gov ID:NCT01365429) as described previously.11 Perfusate samples
The association between human lung glycocalyx shedding during EVLP and graft transplantability and PGD
Human perfusate samples were utilized to assess the extent of glycocalyx shedding in 24 lung allografts during clinical EVLP. Most declined lungs developed significant edema bilaterally or lobar-localized. Figure 1A/B show the time dependent changes of heparan sulfate and syndecan-1 concentration in perfusate for lungs declined for transplant, developed PGD0-1 and PGD after transplant. Regarding glycocalyx stability, the degradation of heparan sulfate over time during EVLP was similar between
Discussion
Adequate endothelial preservation is necessary for effective organ preservation. Sufficient evidence exists demonstrating a clear association between endothelial damage, graft quality and PGD after lung transplant.15 The therapeutic role of glycocalyx preservation to improve post-transplant outcomes has also been well-recognized.16 However, effective therapies for glycocalyx preservation during lung transplantation are still investigational. In this study, we observed that human lung glycocalyx
Conclusion
In this study using a rat model, we demonstrated that HPSE inhibition by SF4 prevented vascular endothelium glycocalyx degradation during EVLP, resulting in improved lung preservation and post-transplant graft quality. Mechanistically, we found that SF4 demonstrated endothelial preservation via the inhibition of proinflammatory NF-κB signaling, implying that pre-treatment of transplantable human lungs with SF4 may promote more favorable patient outcomes.
Disclosure statement
The authors have no conflicts of interest to declare. This study was performed with the approval of the Institutional Animal Care and Use Committee at the University of Pittsburgh.
This study was supported by grants from the research funds of the Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center. The authors thank Dr John Ryan at the University of Pittsburgh for supporting statistical analysis of our data. Also, we thank Dr Shannon Wyszomierski for editing the
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