Plastic Surgery Research Council
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PSRC 60th Annual Meeting
Program and Abstracts

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Phosphodiesterase 5 Inhibition Mitigates I-r Injury In A Model Of Vascularized Composite Allotransplantation
Marc A. Soares, MD, Nakul Rao, MD, Chin Park, MD, Piul S. Rabbani, PhD, Abby Sartor, BA, Pierre B. Saadeh, MD, Daniel J. Ceradini, MD.
NYU, New York, NY, USA.

PURPOSE:
Ischemia reperfusion injury (IRI) induces a significant inflammatory response within the endothelial barrier that regulates tissue survival and homeostasis. This process poses a critical clinical challenge to microsurgery, particularly with regards to vascularized composite allotransplantation. Phosphodiesterase 5 inhibitors (PDE5i) can potentiate vasodilation in ischemic vasculature and suppress inflammatory pathways. If ischemic endothelial injury initiates a pathologic cascade of impaired revascularization, persistent tissue hypoxia, and accelerated inflammation, then we hypothesize that PDE5-inhibition within microvascular flaps will improve tissue physiology in context of IRI.
METHODS:
Endothelial cells (ECs) underwent IRI following 1% hypoxic incubation for 8 hours followed by 6 hours of reperfusion at normoxic conditions. We characterized the effect of FDA-approved doses of sildenafil on vascular inflammatory responses using real-time PCR. Functionally, the influence of PDE5i on the integrity of the endothelial barrier was assessed using diffusion assays. The effect of PDE5i on post-IRI EC proliferation potential was assessed using an MTT assay. Additionally, an adhesion assay was performed to assess the effect of PDE5i on the ability of the vascular endothelium to induce allogenic lymphocyte adherence. In vivo, using an established rat model of VCA, composite flaps were perfused ex-vivo with PDE5i-containing perfusate following procurement and transplanted into allogenic rats. Laser doppler assessed tissue perfusion in the post-operative period. Histologic tissue analysis was correlated with molecular findings.
RESULTS:
PDE5-inhibition decreased vascular inflammatory markers ICAM-1 and MCP-1 following ischemia reperfusion injury (3.4-fold, and 8.1-fold reduction from non-treated controls, respectively p<0.01), while increasing vasculoprotective expression of VEGF and eNOS (2-fold & 4.5-fold respectively compared to non-treated controls p<0.05). Functionally, PDE5i improved EC proliferation following IRI over non-treated ECs by 150% (p<0.05), approaching non-IRI controls. PDE5i reduced IRI-mediated breakdown of the EC barrier by 57% over controls, as well as reducing allogenic lymphocyte adhesion by 23% compared to non-PDE5i controls (p < 0.05 for both). In the immediate post-operative period, PDE5i-allografts demonstrated a 70% increase in vascular perfusion compared to non-treated allografts (0.96 PI v.s. 0.57 PI, p=0.05) while having no deleterious effects on allograft perfusion at 2 weeks. Ongoing studies are evaluating the role of PDE5 inhibition on graft survival and rejection.
CONCLUSION:
PDE5 inhibition using an FDA-approved compounds attenuates vascular damage associated with ischemia-reperfusion injury and may be a rapidly-translatable therapy to improve outcomes in microvascular surgery and allotransplantation.


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