RAGE Mediates LPA Induced Pulmonary Inflammation

 描述(由申请人提供)：暴露于颗粒物(PM)后出现的呼吸功能障碍是世界范围内的一个主要健康问题。工业化国家和发展中国家的环境颗粒物浓度很高，代谢综合征(MetSyn)的发病率也很高。这两种情况在阻塞性肺疾病中的作用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名纽约联邦储备银行的急救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2日至2002年2月10日期间，从8000多名暴露于FDNY的第一反应者身上获得了血清，并可用于生物标记物研究。由于这个生物库是在疾病诊断之前获得的，因此这些生物标志物不是由疾病引起的，可以反映疾病进化过程中活跃的致病途径。我们的研究表明，MetSyn的介体可以预测在接下来的六年中一秒用力呼气量(FEV1)的异常。这种影响不受BMI等混杂因素的影响。为了更好地剖析MetSyn的哪些成分有助于这种作用，我们研究了溶血磷脂酸(LPA)，这是低密度脂蛋白的一种代谢产物。我们最近报道，LPA水平可以预测发生异常的FEV1。我们的合作者施密特博士将RAGE定义为LPA的受体。RAGE在肺中高度表达，在全基因组关联研究中是FEV1的强烈预测因子。我们的初步小鼠实验表明，WTC-PM暴露会导致中性粒细胞增多、FEV1丧失、抵抗力增加和乙酰甲胆碱反应性增加。RAGE缺陷小鼠受到保护，不受WTC-PM影响。吡格列酮是FDA批准的一种PPARɣ激动剂，它抑制RAGE信号转导，并被研究为一种潜在的治疗PM诱导的炎症的方法。我们的初步数据显示，它可以预防WTC-PM诱导的阻力增加、FEV丢失和中性粒细胞增多，但不能防止呼吸道高反应性。假设：RAGE介导LPA诱导的肺部炎症。增加的LPA与PM相互作用，比单独刺激促进更大的炎症。吡格列酮可减轻PM所致的肺损伤。我们的假设将从三个方面进行探讨。目标1将我们的生物标记物观察扩展到1720名在2008年前提交评估的有症状的患者。目的2将利用一系列的小鼠和巨噬细胞模型的功能丧失/获得实验来剖析RAGE对PM/LPA相互作用的贡献。目的3研究吡格列酮治疗是否通过RAGE减轻PM诱导的肺部炎症的早期和晚期影响。这笔赠款产生的数据将为RAGE在调节代谢综合征和肺功能障碍之间的相互作用中扮演的新角色提供新的见解，使我们更接近治疗阻塞性肺疾病的新疗法。

 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.