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.
Subject(s)
Cyclosporine/pharmacology , Drug Synergism , Elafin/pharmacology , Graft Rejection/prevention & control , Microvessels/pathology , Organ Transplantation/adverse effects , Trachea/transplantation , Animals , Apoptosis/drug effects , Blotting, Western , Cell Movement/drug effects , Cells, Cultured , Chemotaxis/drug effects , Complement C3/metabolism , Drug Therapy, Combination , Endothelium, Vascular/drug effects , Female , Graft Rejection/etiology , Graft Rejection/pathology , Graft Survival/drug effects , Human Umbilical Vein Endothelial Cells , Humans , Immunosuppression Therapy , Leukocyte Elastase/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Microcirculation , Microvessels/drug effects , Perfusion , Protease Inhibitors/pharmacology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Wound Healing/drug effectsABSTRACT
Since the identification of the link between pulmonary arterial hypertension (PAH) and exposure to certain drugs and toxins nearly fifty years ago, the expanding landscape of available pharmaceuticals and illicit drugs is further fueling this association. While some causative agents in drugs and toxins associated PAH (D&T-APAH) have been identified, little is known about the exact biology and clinical implications of the disease. In this review, we discuss the historical evidence that links PAH with exposure to anorexinogens, cocaine, and methamphetamines and concentrate on what is known about potential pathogenesis, clinical manifestations, and current management. We conclude that future research should focus on studies looking at clinical outcome and susceptibility factors.