Obesity, Inflammation, and Lung Injury After Lung Transplantation

肺移植后的肥胖、炎症和肺损伤

• 批准号: 8665477
• 负责人: Jason D Christie
• 金额: $ 77.02万
• 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/8665477
• 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; 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; X-Ray Computed Tomography; 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（申请人提供）：肺移植是晚期肺疾病（如间质性肺疾病和慢性阻塞性肺疾病）成人的救命疗法。早期和晚期预后不佳限制了肺移植的成功。原发性移植物功能障碍（PGD）是肺移植术后72小时内发生的急性肺损伤（ALI）的一种形式，是肺移植术后早期死亡的主要原因，并导致慢性同种异体肺移植功能障碍。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有所贡献。肥胖的特点是由于促炎脂肪组织巨噬细胞（ATMs）、T细胞和其他免疫细胞的积累而导致慢性全身性炎症状态。脂肪细胞和atm分泌炎症介质、化学吸引剂和脂肪因子，如瘦素、脂肪素和抵抗素，它们可能促进脂肪的发展