Obesity, Inflammation, and Lung Injury After Lung Transplantation

描述（由申请人提供）：肺移植是一种挽救晚期肺部疾病（如间质性肺病和慢性阻塞性肺病）成人患者生命的治疗方法。肺移植的成功受到早期和晚期不良结局的限制。原发性移植物功能障碍（PGD）是肺移植后72小时内发生的一种急性肺损伤（ALI），是肺移植后早期死亡的主要原因，并导致慢性肺移植物功能障碍。我们最近发现肥胖是PGD的一个新的危险因素。这种关联的机制尚不清楚，但肥胖相关的炎症可能起作用。肥胖症的特征在于由于促炎性脂肪组织巨噬细胞（ATM）、T细胞和其他免疫细胞的积累而导致的慢性全身性炎症状态。脂肪细胞和ATM分泌炎症介质、化学引诱物和脂肪因子，如瘦素、内脂素和内脂素，它们可能有助于脂肪细胞的发展。 阿里我们假设脂肪组织炎症在肺移植手术期间增加并有助于PGD，并且促炎ATM和T细胞驱动这一过程。为了验证我们的假设，我们建议利用肺移植结局组的现有基础设施进行前瞻性队列研究，包括（1）使用定量CT成像测量胸内、内脏和皮下脂肪组织质量，（2）肺移植前后即刻获得的胸内脂肪组织和淋巴结中巨噬细胞和T细胞的免疫表型，以及（3）在三个肺移植中心的参与者中测量血浆和支气管肺泡灌洗液（BAL）中的脂肪因子和细胞因子以及循环和肺室中的淋巴细胞表型（哥伦比亚，宾大和杜克），以实现三个具体目标：具体目标1：确定胸内、内脏和皮下脂肪组织体积与肺移植后PGD风险的相关性;具体目标2：确定脂肪组织炎症是否与PGD的风险相关;和具体目标3：确定血浆和BAL脂肪因子水平是否与PGD的风险相关。本申请提出产生关于脂肪组织炎症在PGD发展中的作用的新知识。该应用是创新的，结合了严格的流行病学和平移方法以及脂肪组织定量CT成像的使用，这可能有助于改善PGD风险的预测并提高移植选择标准。此外，我们建议确定特定的分子，可以在II期临床试验中靶向降低PGD风险，并可能改善肺移植后的结果。

DESCRIPTION (provided by applicant): 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.