RAGE Mediates LPA Induced Pulmonary Inflammation

RAGE 介导 LPA 引起的肺部炎症

• 批准号: 9301639
• 负责人: Anna Nolan
• 金额: $ 42.38万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-07 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9301639
• 关键词: Acute; Advanced Glycosylation End Products; Aftercare; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Binding; Biological Assay; Biological Markers; Biomass; Blood Vessels; Bone Marrow Transplantation; Bronchoalveolar Lavage; Cell Extracts; Chronic lung disease; Complement; Conflict (Psychology); Data; Defect; Developed Countries; Developing Countries; Development; Diet; Disasters; Disease; Early treatment; Evaluation; Evolution; Exposure to; FDA approved; Fire - disasters; Forced expiratory volume function; Functional disorder; Grant; Health; High Fat Diet; High Prevalence; Histology; Hour; IL8 gene; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Injury; Interleukin-10; Investigation; Late Effects; Link; Lipids; Low-Density Lipoproteins; Lung; Lung Inflammation; Lung diseases; Lysophosphatidic Acid Receptors; Measures; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolic syndrome; Military Personnel; Modeling; Mus; Nested Case-Control Study; Neutrophilia; New York; Obstruction; Obstructive Lung Diseases; PPAR gamma; Particulate; Particulate Matter; Pathogenicity; Pathway interactions; Patients; Peritoneal Macrophages; Pioglitazone; Plasma; Population; Prevalence; Pulmonary Function Test/Forced Expiratory Volume 1; Pulmonary Inflammation; Relative Risks; Reporting; Research; Resistance; Respiratory physiology; Retroviridae; Risk Factors; Role; Route; Sample Size; Sampling; Series; Serum; Signal Transduction; Single Nucleotide Polymorphism; Smoke; Smoking History; Spirometry; Stimulus; Time; Wild Type Mouse; Work; airway hyperresponsiveness; biobank; clinical phenotype; cohort; cytokine; disease diagnosis; emergency service responder; experimental study; gain of function; genome wide association study; hazard; in vivo; insight; intraperitoneal; irradiation; loss of function; lung injury; lung preservation; lysophosphatidic acid; macrophage; methacholine; novel; novel therapeutics; oxidation; predictive marker; public health relevance; receptor; receptor for advanced glycation endproducts; reconstitution

 DESCRIPTION (provided by applicant): Development of ventilatory dysfunction following particulate matter (PM) exposure is a major health concern worldwide. Industrialized and developing nations have high ambient particulates and a coexisting high prevalence of metabolic syndrome (MetSyn). The contribution of these two conditions to obstructive pulmonary disease is a topic of considerable importance. The collapse of the World Trade Center (WTC) exposed over 11,000 FDNY first responders to high concentration particulate matter (WTC-PM) at a defined point in time. Between 10/2001-2/2002, serum was obtained on over 8,000 exposed FDNY first responders and is available for biomarker investigation. Since this biobank was obtained prior to disease diagnosis, the biomarkers are not caused by the disease and could reflect pathogenic pathways active during disease evolution. Our research has demonstrated that mediators of MetSyn predict abnormal forced expiratory volume in one second (FEV1) over the subsequent six years. This effect is independent of confounders such as BMI. To better dissect which component of MetSyn contribute to this effect we investigated Lysophosphatidic acid (LPA), a metabolic product of LDL. We recently reported LPA level predicts developing an abnormal FEV1. Our collaborator Dr. Schmidt has defined RAGE as a receptor for LPA. RAGE is highly expressed in the lung and is a strong predictor of FEV1 in genome wide association studies. Our preliminary murine experiments show that WTC-PM exposure produces neutrophilia, loss of FEV1, increased resistance and methacholine reactivity. RAGE deficient mice are protected from these WTC-PM effects. Pioglitazone, an FDA-approved PPARɣ agonist, inhibits RAGE signaling and was studied as a potential treatment against PM-induced inflammation. Our preliminary data showed that it protects against WTC-PM-induced increased resistance, FEV loss, and neutrophilia, but not against airway hyperreactivity. Hypothesis: RAGE mediates LPA induced lung inflammation. Increased LPA interacts with PM to promote greater inflammation than either stimulus alone. Pioglitazone can attenuate PM-induced lung injury. Our hypothesis will be explored in 3 aims. Aim 1 extends our biomarker observations to 1720 symptomatic patients who presented for evaluation before 2008. Aim 2 will use a series of loss/gain of function experiments in murine and macrophage models to dissect the contribution of RAGE to PM/LPA interaction. Aim 3 investigates if pioglitazone treatment attenuates early and late effects of PM-induced pulmonary inflammation via RAGE. Data generated by this grant will provide new insights into the novel role of RAGE in mediating the interaction between metabolic syndrome and pulmonary dysfunction, bringing us closer to new therapies for obstructive lung disease.

 描述（由申请方提供）：颗粒物（PM）暴露后出现排便功能障碍是全球范围内的主要健康问题。工业化国家和发展中国家的环境颗粒物含量高，代谢综合征（MetSyn）的患病率也高。这两种情况对阻塞性肺疾病的影响是一个相当重要的话题。世界贸易中心（WTC）的倒塌使超过11，000名纽约消防局的第一反应人员在规定的时间点暴露于高浓度颗粒物（WTC-PM）。在2001年10月至2002年2月期间，从8，000多名暴露于FDNY的第一反应者中获得血清，并可用于生物标志物研究。由于该生物库是在疾病诊断之前获得的，因此生物标志物不是由疾病引起的，并且可以反映疾病演变期间活跃的致病途径。我们的研究表明，MetSyn的介质预测异常用力呼气容积在一秒钟（FEV 1）在随后的六年。这种影响与BMI等混杂因素无关。为了更好地剖析MetSyn的哪种组分有助于这种效果，我们研究了溶血磷脂酸（LPA），LDL的代谢产物。我们最近报道了LPA水平预示着FEV 1的异常。我们的合作者施密特博士已经将LPA定义为LPA受体。在全基因组关联研究中，FEV 1在肺中高度表达，是FEV 1的强预测因子。我们的初步小鼠实验表明，WTC-PM暴露产生嗜中性粒细胞，FEV 1的损失，增加阻力和乙酰甲胆碱反应性。这些WTC-PM效应可保护WTC-PM缺陷小鼠。吡格列酮是一种FDA批准的PPAR β激动剂，可抑制PPAR β信号传导，并被研究为对抗PM诱导的炎症的潜在治疗药物。我们的初步数据表明，它可以防止WTC-PM诱导的抵抗力增加，FEV损失和嗜中性粒细胞，但不能防止气道高反应性。假设：LPS介导LPA诱导的肺部炎症。增加的LPA与PM相互作用，比单独的任何一种刺激都会促进更大的炎症。吡格列酮可减轻PM所致的肺损伤。我们的假设将在三个目标中进行探索。目标1将我们的生物标志物观察扩展到2008年之前接受评估的1720例有症状的患者。目的2将在小鼠和巨噬细胞模型中使用一系列功能丧失/获得实验，以剖析PMs/LPA相互作用的贡献。目的3：研究吡格列酮治疗是否能通过肺内炎症减轻PM诱导的肺部炎症的早期和晚期效应。这项资助产生的数据将为研究β-内酰胺酶在介导代谢综合征和肺功能障碍之间的相互作用中的新作用提供新的见解，使我们更接近阻塞性肺病的新疗法。