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Am J Transplant. 2015 Jul;15(7):1768-81. doi: 10.1111/ajt.13189. Epub 2015 Feb 27.

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

Author information

1
Veterans Affairs Palo Alto Health Care System, Medical Service, Palo Alto, CA.
2
Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA.
3
Stanford BioADD Laboratory, Stanford, CA.
4
Unité de Défense Innée et Inflammation, Institut Pasteur, Paris, France.
5
INSERM U884, Paris, France.
6
Cardiovascular Institute and Department of Pediatrics, Stanford, CA.

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 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.

KEYWORDS:

basic (laboratory) research/science; calcineurin inhibitor: cyclosporine A (CsA); immunosuppressant; lung transplantation/pulmonology; rejection: acute; rejection: vascular; translational research/science; vascular biology

PMID:
25727073
PMCID:
PMC4474772
DOI:
10.1111/ajt.13189
[Indexed for MEDLINE]
Free PMC Article
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