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

• Published in: American journal of transplantation Vol. 15; no. 7; pp. 1768 - 1781
• Main Authors: Jiang, X., Nguyen, T. T., Tian, W., Sung, Y. K., Yuan, K., Qian, J., Rajadas, J., Sallenave, J.‐M., Nickel, N. P., de Jesus Perez, V., Rabinovitch, M., Nicolls, M. R.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.07.2015
• Subjects: Animals; Apoptosis - drug effects; basic (laboratory) research/science; Blotting, Western; calcineurin inhibitor: cyclosporine A (CsA); Cell Movement - drug effects; Cells, Cultured; Chemotaxis - drug effects; Complement C3 - metabolism; Cyclosporine - pharmacology; Drug Synergism; Drug Therapy, Combination; Elafin - pharmacology; Endothelium, Vascular - drug effects; Female; Graft Rejection - etiology; Graft Rejection - pathology; Graft Rejection - prevention & control; Graft Survival - drug effects; Human Umbilical Vein Endothelial Cells; Humans; immunosuppressant; Immunosuppression Therapy; Ischemia; Leukocyte Elastase - metabolism; lung transplantation/pulmonology; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Microcirculation; Microvessels - drug effects; Microvessels - pathology; Neutrophils; Organ Transplantation - adverse effects; Perfusion; Protease Inhibitors - pharmacology; rejection: acute; rejection: vascular; Rodents; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Trachea - transplantation; translational research/science; Transplants & implants; vascular biology; Wound Healing - drug effects; rejection: vascular; rejection: acute; translational research/science; calcineurin inhibitor: cyclosporine A (CsA); lung transplantation/pulmonology; immunosuppressant; vascular biology; basic (laboratory) research/science
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/ajt.13189

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 airway microvascular perfusion and oxygenation. The therapeutic strategy of targeting neutrophil elastase activity alongside standard immunosuppression during acute rejection episodes may be an effective approach for preventing the development of irreversible fibrotic remodeling. Using a mouse orthotopic tracheal transplantation model, the authors show that cyclosporine fails to protect the microvasculature of airway transplants undergoing acute rejection, but combined therapy with cyclosporine and a neutrophil elastase inhibitor, elafin, synergistically promotes the microvascular perfusion and improves the transplant structural integrity.