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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095686-03
Application #
8235020
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Moore, Timothy M
Project Start
2010-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2012
Total Cost
$356,382
Indirect Cost
$101,874
Name
Palo Alto Institute for Research & Edu, Inc.
Department
Type
DUNS #
624218814
City
Palo Alto
State
CA
Country
United States
Zip Code
94304
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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
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Maxwell, Bryan G; Mooney, Joshua J; Lee, Peter H U et al. (2015) Increased resource use in lung transplant admissions in the lung allocation score era. Am J Respir Crit Care Med 191:302-8
Qian, Jin; Tian, Wen; Jiang, Xinguo et al. (2015) Leukotriene B4 Activates Pulmonary Artery Adventitial Fibroblasts in Pulmonary Hypertension. Hypertension 66:1227-39
Nickel, Nils P; Spiekerkoetter, Edda; Gu, Mingxia et al. (2015) Elafin Reverses Pulmonary Hypertension via Caveolin-1-Dependent Bone Morphogenetic Protein Signaling. Am J Respir Crit Care Med 191:1273-86
Yuan, Ke; Orcholski, Mark E; Panaroni, Cristina et al. (2015) Activation of the Wnt/planar cell polarity pathway is required for pericyte recruitment during pulmonary angiogenesis. Am J Pathol 185:69-84
Jiang, Xinguo; Malkovskiy, Andrey V; Tian, Wen et al. (2014) Promotion of airway anastomotic microvascular regeneration and alleviation of airway ischemia by deferoxamine nanoparticles. Biomaterials 35:803-13

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