Cyclosporine Does Not Prevent Microvascular Loss in Transplantation but Can Synergize With a Neutrophil Elastase Inhibitor, Elafin, to Maintain Graft Perfusion During Acute Rejection.
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.
Veterans Affairs Palo Alto Health Care System, Medical Service, Palo Alto, CA.|Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA.
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Jiang
Veterans Affairs Palo Alto Health Care System, Medical Service, Palo Alto, CA.|Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA.
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Nguyen
Veterans Affairs Palo Alto Health Care System, Medical Service, Palo Alto, CA.|Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA.
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Tian
Veterans Affairs Palo Alto Health Care System, Medical Service, Palo Alto, CA.|Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA.
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Sung
Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA.
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Yuan
Veterans Affairs Palo Alto Health Care System, Medical Service, Palo Alto, CA.|Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA.
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Qian
Stanford BioADD Laboratory, Stanford, CA.
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Rajadas
Unité de Défense Innée et Inflammation, Institut Pasteur, Paris, France.|INSERM U884, Paris, France.
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JM
Sallenave
Cardiovascular Institute and Department of Pediatrics, Stanford, CA.
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Nickel
Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA.
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de Jesus Perez
Cardiovascular Institute and Department of Pediatrics, Stanford, CA.
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Rabinovitch
Veterans Affairs Palo Alto Health Care System, Medical Service, Palo Alto, CA.|Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA.
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Nicolls
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D003176:Complement C3 / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D053492:Elafin / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; D006084:Graft Rejection / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007165:Immunosuppression Therapy; D019272:Leukocyte Elastase / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008833:Microcirculation; D055806:Microvessels / Q000187:drug effects / Q000473:pathology*; D016377:Organ Transplantation / Q000009:adverse effects*; D010477:Perfusion; D011480:Protease Inhibitors / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014132:Trachea / Q000637:transplantation*; D014945:Wound Healing / Q000187:drug effects
D003176:Complement C3; D053492:Elafin; D011480:Protease Inhibitors; D016572:Cyclosporine; D019272:Leukocyte Elastase
basic (laboratory) research/science; calcineurin inhibitor: cyclosporine A (CsA); immunosuppressant; lung transplantation/pulmonology; rejection: acute; rejection: vascular; translational research/science; vascular biology