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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
Program Officer
Craig, Matt
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Biostatistics & Other Math Sci
Schools of Medicine
United States
Zip Code
Singer, Jonathan P; Diamond, Joshua M; Anderson, Michaela R et al. (2018) Frailty phenotypes and mortality after lung transplantation: A prospective cohort study. Am J Transplant 18:1995-2004
Harhay, Michael O; Porcher, Raphaël; Cantu, Edward et al. (2018) An Alternative Approach for the Analysis of Time-to-Event and Survival Outcomes in Pulmonary Medicine. Am J Respir Crit Care Med 198:684-687
Anderson, Brian J; Chesley, Christopher F; Theodore, Miranda et al. (2018) Incidence, risk factors, and clinical implications of post-operative delirium in lung transplant recipients. J Heart Lung Transplant 37:755-762
Panzer, Ariane R; Lynch, Susan V; Langelier, Chaz et al. (2018) Lung Microbiota Is Related to Smoking Status and to Development of Acute Respiratory Distress Syndrome in Critically Ill Trauma Patients. Am J Respir Crit Care Med 197:621-631
Miano, Todd A; Cuker, Adam; Christie, Jason D et al. (2018) Comparative Effectiveness of Enoxaparin vs Dalteparin for Thromboprophylaxis After Traumatic Injury. Chest 153:133-142
Abbas, Arwa A; Young, Jacque C; Clarke, Erik L et al. (2018) Bidirectional transfer of Anelloviridae lineages between graft and host during lung transplantation. Am J Transplant :
Cantu, Edward; Diamond, Joshua M; Suzuki, Yoshikazu et al. (2018) Quantitative Evidence for Revising the Definition of Primary Graft Dysfunction after Lung Transplant. Am J Respir Crit Care Med 197:235-243
Diamond, J M; Cantu, E; Porteous, M K et al. (2017) Peripheral Blood Gene Expression Changes Associated With Primary Graft Dysfunction After Lung Transplantation. Am J Transplant 17:1770-1777
Reilly, John P; Christie, Jason D; Meyer, Nuala J (2017) Fifty Years of Research in ARDS. Genomic Contributions and Opportunities. Am J Respir Crit Care Med 196:1113-1121
Tong, Yubing; Udupa, Jayaram K; Torigian, Drew A et al. (2017) Chest Fat Quantification via CT Based on Standardized Anatomy Space in Adult Lung Transplant Candidates. PLoS One 12:e0168932

Showing the most recent 10 out of 61 publications