Outcomes after lung transplantation remain markedly worse compared to other grafts. Ischemia-reperfusion injury is a neutrophilic form of inflammation that inhibits both short and long-term survival of lung transplant recipients. These observations have led our group to focus on molecular signals that promote neutrophil trafficking into lung grafts following transplantation. In our previous funding period we developed methods to employ intravital 2-photon microscopy to analyze real-time neutrophil trafficking dynamics within ventilated mouse orthotopic lung grafts. This technical innovation allowed us to reveal the critical role that monocytes play in the neutrophil transendothelial migration into reperfused lung grafts and to uncover interactions between neutrophils and other lung graft cells that promote alloimmunity. In this application we propose to examine innate immune signaling pathways that regulate neutrophil trafficking behavior within lung grafts to better understand how these cells prevent tolerance. To this end in Aim 1 we will analyze the role of recipients monocytes and donor Dap12, an adaptor molecule that controls innate immune signaling, in lung graft injury through regulating neutrophil recruitment. We will specifically determine if Dap12 regulates neutrophil transendothelial trafficking and tolerance through controlling the production of cytokines and chemokines in macrophages.
In Aim 2 we propose to define the role of necrotaxis in lung transplants, a specialized form of neutrophil chemotaxis towards dying cells. To execute this aim we will analyze the role of FPR1, a chemokine receptor recently shown to control necrotaxis, to determine if this specific type of neutrophil migratory behavior controls transepithelial trafficking and in turn promotes inflammatory signals that regulate CD4+ T cell polarization and lung transplant rejection.

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 survival of lung transplant recipients is primary graft dysfunction, which is mediated by neutrophil trafficking into transplanted lungs. In this grant proposal we propose to study how neutrophils traffic into lung transplants to find new approaches to improve lung transplant recipient survival.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL094601-08
Application #
9191372
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Harabin, Andrea L
Project Start
2008-12-01
Project End
2018-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
8
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Washington University
Department
Surgery
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Spahn, Jessica H; Li, Wenjun; Bribriesco, Alejandro C et al. (2015) DAP12 expression in lung macrophages mediates ischemia/reperfusion injury by promoting neutrophil extravasation. J Immunol 194:4039-48

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