Novel nutriceuticals relax airway smooth muscle and decrease inflammation in allergic lung disease

新型营养品可放松气道平滑肌并减少过敏性肺部疾病的炎症

基本信息

批准号：
9883958
负责人：
CHARLES W EMALA
金额：
$ 49.05万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9883958
关键词：
A/J Mouse Acute Adrenal Cortex Hormones African American Agonist Airway Disease Allergic Alveolar Macrophages Anaphylaxis Antibodies Antiinflammatory Effect Asthma Attenuated Biological Biological Assay Biological Response Modifier Therapy Bronchoconstriction Bronchodilation CD4 Positive T Lymphocytes Calcium Calcium Oscillations Cell physiology Cells Centers for Disease Control and Prevention (U.S.)Chronic Cleaved cell Clinical Contractile Proteins Coupled Cyclic AMP Cyclic Nucleotides Cytokine Receptors Data Dendritic Cells Dermatophagoides Antigens Diglycerides Drug Kinetics Enzymes Epithelial Cells Extrinsic asthma Family Ginger Ginger extract Human IgE Receptors Immunosuppression Impairment In Situ In Vitro Incidence Individual Inflammation Inflammatory Inhalation Inositol Latino Link Lung Lung Inflammation Lung diseases Lymphocyte Maintenance Therapy Measures Mediating Mediator of activation protein Metabolic Metabolic Pathway Metabolism Modeling Mus Muscle relaxation phase Organ P2Y2 receptor Parents Pathologic Pathway interactions Patients Pharmaceutical Preparations Phenotype Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Phospholipase C Phospholipase C Signaling Pathway Population Poverty Publishing Pyroglyphidae Relaxation Reporting Resistance Route Second Messenger Systems Signal Transduction Slice Smooth Muscle Smooth Muscle Myocytes Steroids Structure Symptoms T-Cell Activation T-Cell Receptor T-Lymphocyte Techniques Therapeutic Toxic effect Trachea airway hyperresponsiveness airway inflammation airway obstruction allergic airway inflammation asthma model asthmatic asthmatic airway smooth muscle cell type constriction cytokine health care settings in vivo insight macrophage methacholine mouse model new therapeutic target novel novel therapeutics phosphodiester phosphoric diester hydrolase recruit respiratory smooth muscle sensitizing antigen shogaol tripolyphosphate

项目摘要

Abstract The Center for Disease Control reported that 7.8% of the US population suffered from asthma in 2015 with much higher incidences in those of African-American or Latino heritage (13.9%) or those below the poverty level (11.1%). For decades, asthma maintenance therapies have relied on inhaled corticosteroids and -agonists, yet nearly 40% of asthmatics have inadequate control of their symptoms. Emerging biologic therapies with antibodies targeting IgE, cytokines and cytokine receptors are limited to small subsets of carefully phenotyped patients, are expensive, and require monthly administration in a health care setting due to anaphylaxis potential. Moreover, no new therapeutic classes of medications that acutely relax airway smooth muscle and bronchoconstriction have been introduced for many decades. Novel therapies that target both airway smooth muscle relaxation and a reduction in allergic lung inflammation would be of enormous clinical benefit. We have identified purified natural components of ginger that acutely relax airway smooth muscle via inhibition of two families of phosphodiesterases that are critical importance in smooth muscle cell function; cyclic nucleotide phosphodiesterases (PDE) and phospholipase C (PLC). Since these compounds undergo metabolism, we have partnered with a world expert in 6-shogaol metabolism to identify human metabolites and even novel synthetic derivatives that retain enhanced potency for airway smooth muscle effects. We have also demonstrated dramatic anti-inflammatory effects of 6-shogaol and inhibition of phospholipase C signaling pathways in macrophages and lymphocytes. Thus, we present a unified cell signaling mechanistic hypothesis of how 6- shogaol derivatives achieve this dual benefit in allergic lung disease: relaxation of airway smooth muscle and anti-inflammation. In aim 1, we will continue our analysis of human metabolites and novel synthetic derivatives of 6-shogaol to identify the structural requirements for PLC and PDE inhibition and smooth muscle relaxation while identifying derivatives with greater potency than the parent 6-shogaol compound in human upper and lower airways. In aim 2, we will demonstrate the mechanism by that these novel metabolites and synthetic derivatives impair activation of human macrophages and CD4+ lymphocytes in vitro and in situ in murine precision cut lung slices. In aim 3, we will unite these mechanistic findings and demonstrate therapeutic potential in vivo. Acute bronchodilatory effects will be demonstrated by the forced oscillatory technique in mouse lungs and chronic anti- inflammatory effects during chronic house dust mite antigen sensitization will be demonstrated. These studies will demonstrate the function, mechanism and therapeutic potential of novel compounds with enhanced potency for targeting two key pathologic features of asthma; airway hyperresponsiveness and lung inflammation.

抽象的美国疾病控制中心报告称，2015 年，7.8% 的美国人口患有哮喘，其中非裔美国人或拉丁裔后裔 (13.9%) 或贫困线以下人群的发病率较高 (11.1%) 几十年来，哮喘维持治疗一直依赖吸入皮质类固醇和 β 激动剂。近 40% 的哮喘患者使用新兴生物疗法无法充分控制其症状。针对 IgE、细胞因子和细胞因子受体的抗体仅限于精心表型的一小部分患者，价格昂贵，并且由于潜在的过敏反应，需要在医疗机构中每月给药。此外，没有新的治疗药物类别可以急剧放松气道平滑肌和几十年来，针对气道平滑的新疗法已经被引入。肌肉放松和减少过敏性肺部炎症将带来巨大的临床益处。鉴定出生姜的纯化天然成分，可通过抑制两种物质来急剧放松气道平滑肌对平滑肌细胞功能至关重要的磷酸二酯酶家族；磷酸二酯酶 (PDE) 和磷脂酶 C (PLC) 由于这些化合物会进行新陈代谢，因此我们有与 6-shogaol 代谢领域的世界专家合作，鉴定人类代谢物，甚至新型合成物我们还证明了保留对气道平滑肌作用的增强效力的衍生物。 6-shogaol 的显着抗炎作用和抑制磷脂酶 C 信号通路因此，我们提出了一个统一的细胞信号传导机制假设 6- 姜烯酚衍生物在过敏性肺病中具有双重功效：松弛气道平滑肌和在目标 1 中，我们将继续分析人类代谢物和新型合成衍生物。 6-姜烯酚以确定 PLC 和 PDE 抑制和平滑肌松弛的结构要求而衍生物比母体 6-shogaol 化合物对人体上部和下部具有更强的效力在目标 2 中，我们将通过这些新型代谢物和合成衍生物来演示其机制。体外和原位小鼠精密切割肺中损害人巨噬细胞和 CD4+ 淋巴细胞的活化在目标 3 中，我们将结合这些机制研究结果并证明其在体内的治疗潜力。支气管扩张作用将通过小鼠肺部的强制振荡技术和慢性抗- 这些研究将证明慢性屋尘螨抗原致敏过程中的炎症效应。将展示具有增强效力的新型化合物的功能、机制和治疗潜力针对哮喘的两个关键病理特征；气道高反应性和肺部炎症。