Lung transplantation is a life-saving therapy for adults with advanced lung diseases, such as interstitial lung disease and chronic obstructive pulmonary disease. The success of lung transplantation is limited by poor early and late outcomes. Primary graft dysfunction (PGD), a form of acute lung injury (ALI) occurring within 72 hours of lung transplantation, is the leading cause of death early after lung transplantation and contributes to chronic lung allograft dysfunction. We recently identified obesity as a novel risk factor for PGD. The mechanism underlying this association is not known, but obesity-related inflammation could contribute. Obesity is characterized by a chronic systemic inflammatory state due to the accumulation of pro-inflammatory adipose tissue macrophages (ATMs), T cells, and other immune cells. Adipocytes and ATMs secrete inflammatory mediators, chemoattractants, and adipokines, such as leptin, visfatin, and resistin, that could contribute to the development of ALI. We hypothesize that adipose tissue inflammation increases during lung transplant surgery and contributes to PGD, and that pro-inflammatory ATMs and T cells drive this process. To test our hypothesis, we propose leverage the existing infrastructure of the Lung Transplant Outcomes Group perform a prospective cohort study that includes (1) measurement of intrathoracic, visceral, and subcutaneous adipose tissue mass using quantitative CT imaging, (2) immunophenotyping of macrophages and T cells from intrathoracic adipose tissue and lymph nodes obtained immediately before and after lung transplantation, and (3) measurement of adipokines and cytokines in plasma and bronchoalveolar lavage (BAL) fluid and lymphocyte phenotypes in the circulating and lung compartments in participants at three lung transplant centers (Columbia, Penn, and Duke) to accomplish three Specific Aims:
Specific Aim 1 : Determine the associations of intrathoracic, visceral, and subcutaneous adipose tissue volume with the risk of PGD after lung transplantation;
Specific Aim 2 : Determine whether adipose tissue inflammation is associated with the risk of PGD;
and Specific Aim 3 : Determine whether plasma and BAL adipokine levels are associated with the risk of PGD. This application proposes to generate new knowledge on the role of adipose tissue inflammation in the development of PGD. The application is innovative in combining rigorous epidemiologic and translational approaches and the use of quantitative CT imaging of adipose tissue, which could help to improve the prediction of PGD risk and enhance transplant selection criteria. In addition, we propose to identify specific molecules that could be targeted in phase II clinical trials to decrease PGD risk and potentially improve outcomes after lung transplantation.

Public Health Relevance

One out of 5 adults who undergo lung transplantation dies within the first year of transplantation, most commonly as a consequence of damage to the new lungs early after transplantation. Overweight and obese adults undergoing lung transplantation are twice as likely as others to suffer from this early damage. We will determine if inflammation in fat tissue is responsible for this early damage so that we can develop treatments aimed at decreasing fat inflammation and thereby avoid damage to the transplanted lungs.

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
Eu, Jerry Pc
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University (N.Y.)
Internal Medicine/Medicine
Schools of Medicine
New York
United States
Zip Code
Podolanczuk, Anna J; Oelsner, Elizabeth C; Barr, R Graham et al. (2016) High attenuation areas on chest computed tomography in community-dwelling adults: the MESA study. Eur Respir J 48:1442-1452
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
Sell, Jessica L; Bacchetta, Matthew; Goldfarb, Samuel B et al. (2016) Short Stature and Access to Lung Transplantation in the United States. A Cohort Study. Am J Respir Crit Care Med 193:681-8
Palakshappa, Jessica A; Anderson, Brian J; Reilly, John P et al. (2016) Low Plasma Levels of Adiponectin Do Not Explain Acute Respiratory Distress Syndrome Risk: a Prospective Cohort Study of Patients with Severe Sepsis. Crit Care 20:71
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
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
Kliment, Corrine R; Araki, Tetsuro; Doyle, Tracy J et al. (2015) A comparison of visual and quantitative methods to identify interstitial lung abnormalities. BMC Pulm Med 15:134

Showing the most recent 10 out of 23 publications