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 have identified obesity as a novel risk facto 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. The Lung Transplant Body Composition (LTBC) study is a multicenter cohort study testing the hypothesis that adipose tissue inflammation increases during lung transplant surgery and contributes to PGD, and specifically that pro-inflammatory ATMs and T cells drive this process. In this K24 Award, I propose an ancillary study to the LTBC study that will test the hypotheses that the inflammatory profile of subcutaneous adipose tissue obtained prior to lung transpalntation can (1) help identify individuals with an inflammatory profile in intrathoracic adipose tissue obtained during lung transplant surgery, and (2) is associated with greater disease severity in interstitial lung disease. With this K24 Award, I will develop additional mentorship skills and directly mentor additional trainees throughout the Award period. I also propose to develop the Pulmonary Fibrosis Foundation Scholars Program, a multicenter mentorship program designed to train fellows and junior faculty in clinical and translational patient-oriented research methods in interstitial lung disease. The proposal is innovative in nesting a translational study examining adipose tissue inflammation in an epidemiological cohort study of lung transplant candidates with interstitial lung disease. This work will lead to phase II clinical trials to decrease PGD risk in at-risk candidates identified through an inflammatory subcutaneous adipose tissue profile.
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 subcutaneous fat can help identify those with inflammation in the fat in the chest at the time of transplant surgery.
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