Introduction: Vascular composite allotransplantation (VCA) of the limb involves cold and warm ischemia, further limiting organ availability beyond the constraints of blood type, HLA compatibility, age, size, skin color and gender. No current therapy exists to mitigate ischemia reperfusion injury (IRI). We have previously demonstrated histone deacetylase inhibition (HDACi) mitigates renal IRI, and we wished to assess the impact of HDACi on limb IRI tolerance.

Methods: Female wild type C57BL/6 mice were treated with pan-HDACi trichostain A(TSA), class I HDACi(MS-275), or control (DMSO) at 16h & 30m pre-IRI. Mice were subjected to 60m of unilateral limb ischemia under strict temperature control at 36.5^oC. Ischemia was performed with the placement of a dental band just proximal to the knee joint, with complete vascular occlusion, and subsequent band lysis. Histopathologic analysis was conducted at 24h post injury, and scored based on muscle necrosis and granulocyte demarcation. Contralateral limbs served as internal controls.

Results: TSA pre-treatment yielded protection from limb warm IRI (freedom from injury n=4/8 versus n=2/8) (Figure1a). MS-275 treatment yielded a greater degree of protection (freedom from injury n=8/8 versus n=3/8 (Figure1b).

Conclusion: Pan- and class I-HDACi mitigates limb injury after IRI with class I inhibition proving more effective. Further studies will focus on HDACi protection from cold ischemia in a VCA model as the use of additional endpoints such as serum myoglobin, and tissue oxygenation via ultrasound are underway.

CITATION INFORMATION: Concors S., Aufhauser D., Murken D., Wang Z., Ge G., Bhatti T., Hancock W., Levine M. Histone Deacetylase Inhibition Mitigates Limb Ischemia Reperfusion Injury Am J Transplant. 2017;17 (suppl 3).

« Back to 2018 American Transplant Congress