Cyclosporine Does Not Prevent Microvascular Loss in Transplantation but Can Synergize With a Neutrophil Elastase Inhibitor, Elafin, to Maintain Graft Perfusion During Acute Rejection

American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
Xinguo JiangMark R Nicolls

Abstract

The loss of a functional microvascular bed in rejecting solid organ transplants is correlated with fibrotic remodeling and chronic rejection; in lung allografts, this pathology is predicted by bronchoalveolar fluid neutrophilia which suggests a role for polymorphonuclear cells in microcirculatory injury. In a mouse orthotopic tracheal transplant model, cyclosporine, which primarily inhibits T cells, failed as a monotherapy for preventing microvessel rejection and graft ischemia. To target neutrophil action that may be contributing to vascular injury, we examined the effect of a neutrophil elastase inhibitor, elafin, on the microvascular health of transplant tissue. We showed that elafin monotherapy prolonged microvascular perfusion and enhanced tissue oxygenation while diminishing the infiltration of neutrophils and macrophages and decreasing tissue deposition of complement C3 and the membrane attack complex, C5b-9. Elafin was also found to promote angiogenesis through activation of the extracellular signal-regulated kinase (ERK) signaling pathway but was insufficient as a single agent to completely prevent tissue ischemia during acute rejection episodes. However, when combined with cyclosporine, elafin effectively preserved ai...Continue Reading

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Citations

Aug 20, 2017·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Ellyse CipollaRagini Vittal
Mar 10, 2016·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Hongmei GuRagini Vittal
Sep 25, 2019·Stem Cell Research & Therapy·Mohammad Afzal KhanDieter Clemens Broering
Mar 12, 2016·Current Opinion in Organ Transplantation·Mark R NicollsXinguo Jiang

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