Microvascular loss may be an unappreciated root cause of chronic rejection for all solid organ transplants. There is currently no knowledge about how airway microvasculature is repaired immediately following transplantation or alloimmune injury. Maintaining healthy microvasculature in lung allografts could be key for preventing terminal airway fibrosis, also known as the bronchiolitis obliterans syndrome (BOS). Therefore understanding how endothelial cells contribute to vascular repair may facilitate therapies which enhance microvascular recovery and, in so doing, prevent BOS. Mouse orthotopic tracheal transplantation (OTT) is an ideal model for examining microvascular loss in airways and how recipient-derived progenitor cells contribute to revascularization. Both human and mouse airways are hypoxic following transplantation. In OTT, rising hypoxia-inducible factor 1 alpha (HIF-1alpha) is observed with progressive hypoxia and may be responsible for the connection between recipient and donor circulations soon after transplantation. This proposal will determine if increased HIF-1alpha, as well as allospecific T cells, induce angiogenic signals that promote the influx of putatively reparative endothelial cells bearing the endothelial antigen, Tie2. Lineage analysis will be used to determine the fate of migrating endothelial cells in restoration of the recipient-derived microvasculature. The global hypothesis to be tested is that airway transplant recipients respond to graft- derived HIF-1alpha signals by sending Tie2 cells that subsequently incorporate into graft microvasculature.
Specific Aim 1 will use mice with endothelial-specific expression of Cre-recombinase (Tie-2 Cre) intercrossed with reporter mice Rosa26R (loxP Stop loxp yfp) to determine the fate of recipient Tie2 cells migrating into donor airways.
This aim will also study the effects of hypoxia and T cell subsets on Tie2 cell migration.
Specific Aim 2 will elucidate the effects of HIF-1alpha, through gain- and loss- of function experiments, on airway revascularization, tissue pO2, graft rejection, and Tie2 cell migration. The results of these studies are likely to reveal fundamental mechanisms of vascular repair in airways and may promote novel angiogenic therapies that limit fibrogenesis.
While lung transplantation is a cure for end-stage pulmonary disease, the majority of patients undergoing this procedure will eventually die from scarring of the airways. This may happen, in part, because of a temporary loss of airway blood flow. The proposed studies will investigate how the body's normal reparative processes resupply airways with blood vessels and how this process might be utilized to prevent airway injury.
|Hsu, Joe L; Manouvakhova, Olga V; Clemons, Karl V et al. (2018) Microhemorrhage-associated tissue iron enhances the risk for Aspergillus fumigatus invasion in a mouse model of airway transplantation. Sci Transl Med 10:|
|Jiang, Xinguo; Tian, Wen; Tu, Allen B et al. (2018) Endothelial HIF-2? is Required for the Maintenance of Airway Microvasculature. Circulation :|
|Lin, Y-C; Sung, Y K; Jiang, X et al. (2017) Simultaneously Targeting Myofibroblast Contractility and Extracellular Matrix Cross-Linking as a Therapeutic Concept in Airway Fibrosis. Am J Transplant 17:1229-1241|
|Pasupneti, S; Manouvakhova, O; Nicolls, M R et al. (2017) Aspergillus-related pulmonary diseases in lung transplantation. Med Mycol 55:96-102|
|Lama, Vibha N; Belperio, John A; Christie, Jason D et al. (2017) Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop. JCI Insight 2:|
|Zamora, Martin R; Martinu, Tereza; Nicolls, Mark R (2017) Introduction to the 59th Annual Thomas L. Petty Aspen Lung Conference. Lung Transplantation: Opportunities for Repair and Regeneration. Ann Am Thorac Soc 14:S209|
|Nicolls, Mark R; Dhillon, Gundeep S; Daddi, Niccolò (2016) A Critical Role for Airway Microvessels in Lung Transplantation. Am J Respir Crit Care Med 193:479-81|
|Mooney, J J; Hedlin, H; Mohabir, P K et al. (2016) Lung Quality and Utilization in Controlled Donation After Circulatory Determination of Death Within the United States. Am J Transplant 16:1207-15|
|Nicolls, Mark R; Hsu, Joe L; Jiang, Xinguo (2016) Microvascular injury after lung transplantation. Curr Opin Organ Transplant 21:279-84|
|Jothimuthu, Preetha; Hsu, Joe L; Chen, Robert et al. (2016) Enhanced Electrochemical Sensing with Carbon Nanotubes Modified with Bismuth and Magnetic Nanoparticles in a Lab-on-a-Chip. ChemNanoMat 2:904-910|
Showing the most recent 10 out of 54 publications