Obesity, Inflammation, and Lung Injury After Lung Transplantation

描述(申请人提供)：肺移植是一种救命疗法，适用于患有晚期肺部疾病的成年人，如间质性肺疾病和慢性阻塞性肺疾病。肺移植的成功受到早期和晚期效果不佳的限制。原发移植物功能障碍(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，也是慢性移植肺功能障碍的原因之一。我们最近发现肥胖是PGD的一个新的危险因素。这种联系背后的机制尚不清楚，但肥胖相关的炎症可能起到了作用。肥胖的特征是由于促炎脂肪组织巨噬细胞(ATM)、T细胞和其他免疫细胞的积聚而导致的慢性全身炎症状态。脂肪细胞和ATM分泌炎性介质、趋化物质和脂肪因子，如瘦素、内脂素和抵抗素，它们可能有助于 阿里。我们假设，在肺移植手术期间，脂肪组织炎症增加并促进了PGD，而促炎ATM和T细胞驱动了这一过程。为了验证我们的假设，我们建议利用肺移植结果小组现有的基础设施进行一项前瞻性队列研究，包括(1)使用定量CT成像测量胸腔内、内脏和皮下脂肪组织质量，(2)对肺移植前和肺移植后立即获得的胸腔内脂肪组织和淋巴结中的巨噬细胞和T细胞进行免疫表型鉴定，以及(3)测量三个肺移植中心(哥伦比亚、宾夕法尼亚和杜克)参与者循环和肺腔内脂肪和淋巴细胞表型的血浆和支气管肺泡灌洗液(BAL)中的脂肪因子和细胞因子，以实现三个特定目标：特定目标1：确定胸腔内、内脏、胸腔内T细胞的相关性和皮下脂肪组织体积与肺移植后PGD的风险；特定目标2：确定脂肪组织炎症是否与PGD风险相关；特定目标3：确定血浆和BAL脂肪因子水平是否与PGD风险相关。这项应用提出了关于脂肪组织炎症在PGD发展中的作用的新知识。该应用程序在结合严格的流行病学和翻译方法以及使用脂肪组织的定量CT成像方面具有创新性，有助于提高PGD风险的预测和提高移植选择标准。此外，我们建议确定可以在II期临床试验中作为靶点的特定分子，以降低PGD风险并潜在地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.