Primary graft dysfunction (PGD) is severe acute lung injury occurring in the days after lung transplantation and is characterized by diffuse pulmonary edema and profound hypoxemia. PGD has a major impact on outcomes following lung transplantation, markedly increasing early morbidity, mortality, and cost. Thus, reduction in the incidence of PGD would dramatically improve outcomes following lung transplantation. During the prior R01 cycle, we established donor smoking history, measured by communication through a proxy, as a significant risk factor for subsequent PGD of the allograft, as well as useful predictor of PGD. Concordant with our findings, cigarette smoke exposure has recently been shown to predispose to acute lung injury in the trauma population. However, a strategy of excluding donors with a smoking history from the lung donor pool leads to an overall increased mortality for those awaiting lung transplantation;therefore, better quantitative measurement of donor smoking on PGD risk, and enhanced understand the mechanisms by which smoking contributes to PGD are necessary to improve transplant outcomes. We hypothesize the effect of donor smoke exposure on PGD risk can be more fully quantified by biochemical measures, and that the increased risk of PGD in smoking donors is linked to alterations of the donor microbiome and effects on resident lung immune cell populations. To address these hypotheses, we will expand our research infrastructure established in the prior R01 cycle to define the quantitative relationship between donor smoke exposure and PGD;determine the relationships between alterations in resident lung immune cell populations, donor smoking status, and PGD;and define the relationships between allograft microbiome populations, donor smoking status, and PGD.
Our aims will establish the role of urinary biomarkers of smoke exposure in donor risk stratification to safely expand the donor pool. As well, we will define the role of novel mechanisms in PGD risk that are amenable to therapies aimed at reducing the elevated risk seen in donors with smoke exposure.

Public Health Relevance

Primary graft dysfunction (PGD) is a form of severe acute lung injury (shock lung) occurring in the days after lung transplantation that is characterized b diffuse pulmonary edema, profound hypoxemia, and higher early morbidity, mortality, and cost. Thus, reduction in the risk of PGD would dramatically improve outcomes following lung transplantation. Building on our findings during the prior R01 cycle, we now seek to quantify the relationship of donor smoke exposure with greater PGD risk by measuring urine markers to better match donors to recipients, and to create new knowledge of the mechanisms by which smoking contributes to PGD by defining the contributions of the lung microbiome and novel innate lung immune cells.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL087115-06A1
Application #
8760368
Study Section
Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
Program Officer
Eu, Jerry Pc
Project Start
2006-12-01
Project End
2018-06-30
Budget Start
2014-08-01
Budget End
2015-06-30
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Biostatistics & Other Math Sci
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Diamond, J M; Shah, R J; Cantu 3rd, E et al. (2016) Survey of Lung Transplant Community's Views on Primary Graft Dysfunction. Am J Transplant 16:724-6
Diamond, Joshua M; Porteous, Mary K; Jackson Roberts 2nd, L et al. (2016) The relationship between plasma lipid peroxidation products and primary graft dysfunction after lung transplantation is modified by donor smoking and reperfusion hyperoxia. J Heart Lung Transplant 35:500-7
Cantu, E; Suzuki, Y; Diamond, J M et al. (2016) Protein Quantitative Trait Loci Analysis Identifies Genetic Variation in the Innate Immune Regulator TOLLIP in Post-Lung Transplant Primary Graft Dysfunction Risk. Am J Transplant 16:833-40
Abbas, A A; Diamond, J M; Chehoud, C et al. (2016) The Perioperative Lung Transplant Virome: Torque Teno Viruses are Elevated in Donor Lungs and Show Divergent Dynamics In Primary Graft Dysfunction. Am J Transplant :
Monticelli, Laurel A; Buck, Michael D; Flamar, Anne-Laure et al. (2016) Arginase 1 is an innate lymphoid-cell-intrinsic metabolic checkpoint controlling type 2 inflammation. Nat Immunol 17:656-65
Sayah, David M; Mallavia, Beñat; Liu, Fengchun et al. (2015) Neutrophil extracellular traps are pathogenic in primary graft dysfunction after lung transplantation. Am J Respir Crit Care Med 191:455-63
Ferguson, Jane F; Meyer, Nuala J; Qu, Liming et al. (2015) Integrative genomics identifies 7p11.2 as a novel locus for fever and clinical stress response in humans. Hum Mol Genet 24:1801-12
Eberlein, Michael; Reed, Robert M; Bolukbas, Servet et al. (2015) Lung size mismatch and primary graft dysfunction after bilateral lung transplantation. J Heart Lung Transplant 34:233-40
Zhong, Ming; Zhang, Hanrui; Reilly, John P et al. (2015) ABO Blood Group as a Model for Platelet Glycan Modification in Arterial Thrombosis. Arterioscler Thromb Vasc Biol 35:1570-8
Shah, R J; Diamond, J M; Cantu, E et al. (2015) Objective Estimates Improve Risk Stratification for Primary Graft Dysfunction after Lung Transplantation. Am J Transplant 15:2188-96

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