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)
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
Project End
Budget Start
Budget End
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
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
Cantu, Edward; Shah, Rupal J; Lin, Wei et al. (2015) Oxidant stress regulatory genetic variation in recipients and donors contributes to risk of primary graft dysfunction after lung transplantation. J Thorac Cardiovasc Surg 149:596-602
Wong, Hector R; Lindsell, Christopher J; Pettilä, Ville et al. (2014) A multibiomarker-based outcome risk stratification model for adult septic shock*. Crit Care Med 42:781-9
Diamond, Joshua M; Akimova, Tatiana; Kazi, Altaf et al. (2014) Genetic variation in the prostaglandin E2 pathway is associated with primary graft dysfunction. Am J Respir Crit Care Med 189:567-75
Shah, Rupal J; Christie, Jason D (2014) Response. Chest 145:193
Cohen, David G; Christie, Jason D; Anderson, Brian J et al. (2014) Cognitive function, mental health, and health-related quality of life after lung transplantation. Ann Am Thorac Soc 11:522-30
Singer, Jonathan P; Peterson, Eric R; Snyder, Mark E et al. (2014) Body composition and mortality after adult lung transplantation in the United States. Am J Respir Crit Care Med 190:1012-21
Chatterjee, Shampa; Nieman, Gary F; Christie, Jason D et al. (2014) Shear stress-related mechanosignaling with lung ischemia: lessons from basic research can inform lung transplantation. Am J Physiol Lung Cell Mol Physiol 307:L668-80
Shah, Rupal J; Emtiazjoo, Amir M; Diamond, Joshua M et al. (2014) Plasma complement levels are associated with primary graft dysfunction and mortality after lung transplantation. Am J Respir Crit Care Med 189:1564-7
Shah, R J; Wickersham, N; Lederer, D J et al. (2014) Preoperative plasma club (clara) cell secretory protein levels are associated with primary graft dysfunction after lung transplantation. Am J Transplant 14:446-52

Showing the most recent 10 out of 29 publications