Outcomes for lung transplant recipients remain significantly worse when compared to other organ recipients. Lung allograft injury in the first 72 hours post-transplant, also termed Primary Graft Dysfunction, is the leading cause for early mortality following lung transplantation and has also been shown to be a risk factor for chronic lung rejection. Ischemia-reperfusion injury is the leading cause of Primary Graft Dysfunction but the mechanisms that control this type of injury remain unclear. To address this problem we developed an orthotopic vascularized aerated lung transplant method that models Primary Graft Dysfunction in humans. New data from this model shows that a subset of IL-10+ TNF-?- neutrophils accumulate in graft tissue shortly after transplantation and may protect against lung graft ischemia-reperfusion injury. We observed that IL-10+ TNF-? - neutrophils are the predominant IL-10+ cell type following lung transplantation and that their development is dependent on stress-induced or 'emergency granulopiesis'. In the absence of IL-10 expression in the recipient lung graft injury was severe indicating IL-10 is important to prevent lung graft ischemia reperfusion injury. We hypothesize that emergency granulopoiesis is required to generate IL-10+ neutrophils to prevent lung graft ischemia reperfusion injury. We have three specific aims.
Our first aim i s to examine factors that regulate the production of IL-10+ neutrophils in lung recipients.
Our second aim i s to develop IL-10+ neutrophil-based strategies to prevent or treat lung graft ischemia reperfusion injury.
Our third aim i s to assess patterns of IL-10 and TNF-? expression in the peripheral blood neutrophils of human lung recipients with varying degrees of primary graft dysfunction.

Public Health Relevance

Lung transplantation has become an established therapy for patients suffering from end stage lung disease. Lung transplant recipient survival is still poor when compared to recipients of other solid organs such as the kidney, liver and heart. A major obstacle to the long-term survival of lung transplant recipients is Primary Graft Dysfunction. We propose to study how neutrophils can be re-programmed to prevent Primary Graft Dysfunction.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL113436-02
Application #
8666608
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Eu, Jerry Pc
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Ibrahim, Mohsen; Wang, Xingan; Puyo, Carlos A et al. (2015) Human recombinant apyrase therapy protects against canine pulmonary ischemia-reperfusion injury. J Heart Lung Transplant 34:247-53
Krupnick, Alexander Sasha; Lin, Xue; Li, Wenjun et al. (2014) Central memory CD8+ T lymphocytes mediate lung allograft acceptance. J Clin Invest 124:1130-43
Todd, Jamie L; Wang, Xingan; Sugimoto, Seichiro et al. (2014) Hyaluronan contributes to bronchiolitis obliterans syndrome and stimulates lung allograft rejection through activation of innate immunity. Am J Respir Crit Care Med 189:556-66
Gelman, A E; Scozzi, D (2013) Activating killers by stimulating RAGE. Am J Transplant 13:2237-8
Chen, D L; Wang, X; Yamamoto, S et al. (2013) Increased T cell glucose uptake reflects acute rejection in lung grafts. Am J Transplant 13:2540-9