Microvascular loss may be an unappreciated root cause of chronic rejection for all solid organ transplants. As the only solid organ transplant that does not undergo primary systemic arterial revascularization at the time of surgery, lung transplants rely on the establishment of a microcirculation and are especially vulnerable to the effects of microvascular loss. Microangiopathy, with its attendant ischemia, can lead to tissue infarction and airway fibrosis. Maintaining healthy vasculature in lung allografts may be critical for preventing terminal airway fibrosis, also known as the bronchiolitis obliterans syndrome. This condition is the major obstacle to lung transplant success and affects up to 60% of patients surviving five years. The role of complement in causing acute microvascular loss and ischemia during rejection has not been studied previously in transplantation. Mouse orthotopic tracheal transplantation is an ideal model for parsing the role of airway vasculature in rejection. Prior to the development of airway fibrosis in rejecting allografts, C3 deposits on the vascular endothelium just as tissue hypoxia is first detected. With the eventual destruction of vessels, microvascular blood flow to the graft stops altogether for several days. Preliminary results suggest that complement deficiency and complement inhibition lead to markedly improved tissue oxygenation, diminished airway remodeling and accelerated vascular repair. These results collectively suggest that complement activity is harmful, in part, because complement-mediated vascular injury results in graft ischemia. This project examines two pivotal steps in the complement cascade, C3 and the membrane attack complex (MAC), and how each of these steps specifically contributes to airway vascular injury and repair. Complementary regulatory proteins, including CD55 and CD59, ordinarily regulate complement activity. The down-regulation of these regulatory proteins on vascular endothelium in rejection may be key to why complement activation damages the vasculature during rejection. The global hypothesis to be tested in this project is that controlling complement activation at the level of C3 and MAC activation will limit airway ischemia and promote vascular repair.
Specific Aim 1 will be to determine how C3 activation impacts graft hypoxia, vascular perfusion and airway remodeling in transplant recipients and tests the hypothesis that the deleterious impact of C3 convertase activation on the functional microcirculation of rejecting airways is normally inhibited by CD55 activity.
Sub aims will investigate how both global and targeted reduction of C3 convertase activation and regulation affects vascular flow to the transplant.
Specific Aim 2 will be to determine how MAC activation impacts graft hypoxia, vascular perfusion and airway remodeling in transplant rejection and tests the hypothesis that the deleterious impact of MAC assembly on the functional microcirculation of rejecting airways is ordinarily controlled by CD59 activity.
Sub aims will study the impact of interfering with MAC assembly and regulation on vascular flow to the airways. Finally, Specific Aim 3 will be to determine how complement inhibition therapeutically hastens the repair of graft microvasculature following rejection.
This Aim tests the hypothesis that complement inhibition facilitates the repair of the graft microvasculature by promoting the influx of recipient-derived endothelial cells.
This aim utilizes mice with endothelial-specific expression of Cre-recombinase (Tie-2 Cre) intercrossed with reporter mice Rosa26R (loxP Stop loxp yfp) to create graft recipients which have permanently labeled endothelial cells. Preventing airway ischemia through knowledge gained about complement activity and regulation in rejection may promote useful and potentially life-saving therapies for lung transplant recipients.
|Jiang, X; Nguyen, T T; Tian, W et al. (2015) Cyclosporine Does Not Prevent Microvascular Loss in Transplantation but Can Synergize With a Neutrophil Elastase Inhibitor, Elafin, to Maintain Graft Perfusion During Acute Rejection. Am J Transplant 15:1768-81|
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|Khan, Mohammad A; Maasch, Christian; Vater, Axel et al. (2013) Targeting complement component 5a promotes vascular integrity and limits airway remodeling. Proc Natl Acad Sci U S A 110:6061-6|
|Khan, Mohammad A; Jiang, Xinguo; Dhillon, Gundeep et al. (2011) CD4+ T cells and complement independently mediate graft ischemia in the rejection of mouse orthotopic tracheal transplants. Circ Res 109:1290-301|