Obesity, Inflammation, and Lung Injury After Lung Transplantation

肺移植后的肥胖、炎症和肺损伤

• 批准号: 8504114
• 负责人: Jason D Christie
• 金额: $ 80.55万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-23 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8504114
• 关键词: Acute; Acute Lung Injury; Adipocytes; Adipose tissue; Adult; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Atherosclerosis; Autoimmunity; Biological Assay; Blood; Bronchiolitis Obliterans; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; CD8B1 gene; Cause of Death; Cells; Chemotactic Factors; Chronic; Chronic Obstructive Airway Disease; Cohort Studies; Critical Illness; DNA Binding; Data Collection; Densitometry; Development; Epidemiology; Fatty acid glycerol esters; Flow Cytometry; Functional disorder; Gene Expression; Genes; Hour; Image; Immune; Immunophenotyping; Inflammation; Inflammation Mediators; Inflammatory; Injury; Interstitial Lung Diseases; Kidney Transplantation; Knowledge; Leptin; Life; Lung; Lung Transplantation; Lung diseases; Lymphocyte; Measurement; Measures; Metabolic syndrome; Morbidity - disease rate; Obesity; Operative Surgical Procedures; Outcome; Overweight; Participant; Peroxisome Proliferator-Activated Receptors; Phase II Clinical Trials; Phenotype; Pioglitazone; Plasma; Prevention; Process; Production; Pulmonary Circulation; Regulatory T-Lymphocyte; Reperfusion Injury; Research Infrastructure; Risk; Risk Factors; Role; Selection Criteria; Syndrome; T cell response; T-Lymphocyte; Testing; Tissues; Transplant Recipients; Transplantation; Visceral; Work; adipokines; adiponectin; cytokine; improved; innovation; liver transplantation; lung allograft; lung injury; lymph nodes; macrophage; mortality; nonalcoholic steatohepatitis; novel; prevent; prospective; protein expression; public health relevance; resistin; subcutaneous; success; translational approach

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.

描述（由申请人提供）：肺移植是针对患有晚期肺部疾病的成年人的救生疗法，例如间质性肺部疾病和慢性阻塞性肺部疾病。肺移植的成功受到早期和晚期不良结局的限制。原发性移植功能障碍（PGD）是一种在肺移植后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，并导致慢性肺同种异体移植功能障碍。我们最近将肥胖症确定为PGD的新风险因素。该关联的基础机制尚不清楚，但与肥胖相关的炎症可能会产生。肥胖的特征是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，肥胖症的特征是慢性全身性炎症状态。脂肪细胞和ATMS分泌炎症介质，化学吸引剂和脂肪因子，例如瘦素，粘蛋白和抵抗素，可能有助于发展 阿里。我们假设在肺移植手术期间脂肪组织炎症增加并有助于PGD，并且促炎的ATM和T细胞驱动了这一过程。为了检验我们的假设，我们提出杠杆肺移植结果的现有基础架构组进行了一项前瞻性研究研究，其中包括（1）使用定量CT成像的定量CT成像，（2）内部内部的细胞和内部型细胞的近原化细胞和T型脂肪组织质量的测量（1），（2）内部粘液液的底膜和TIMPAITAIS脂肪组织质量。以及（3）在血浆和支气管肺泡灌洗中的脂肪因子和细胞因子测量的测量，在循环和肺部的三个肺部移植中心（哥伦比亚，佩恩和杜克）的参与者中，参与者的循环和肺部中的淋巴细胞和淋巴细胞表型，以完成三个肺部移植中心，以达到三个特定特定的目标：内脏和皮下脂肪组织体积，肺移植后具有PGD的风险；具体目标2：确定脂肪组织炎症是否与PGD风险有关；和特定目标3：确定血浆和脂肪因子水平是否与PGD风险有关。该应用程序提出了有关脂肪组织炎症在PGD发展中的作用的新知识。该应用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，这可能有助于改善PGD风险的预测并增强移植选择标准。此外，我们建议确定可以在II期临床试验中针对的特定分子，以降低PGD风险并有可能改善肺移植后的预后。