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

摘要 疾病控制中心报告说，2015年有7.8%的美国人口患有哮喘， 非洲裔美国人或拉丁裔美国人（13.9%）或贫困线以下的人发病率较高 (11.1%).几十年来，哮喘维持治疗一直依赖于吸入性皮质类固醇和β-受体激动剂，然而， 近40%的哮喘患者无法充分控制其症状。新兴的生物疗法， 靶向IgE、细胞因子和细胞因子受体的抗体仅限于小的亚群， 患者，是昂贵的，并且由于过敏反应的可能性，需要在卫生保健环境中每月给药。 此外，没有新的治疗类别的药物，急性放松气道平滑肌， 支气管收缩已经引入了几十年。靶向气道平滑 肌肉松弛和变应性肺部炎症的减少将具有巨大的临床益处。我们有 确定了生姜的纯化天然成分，通过抑制两种 对平滑肌细胞功能至关重要的磷酸二酯酶家族;环核苷酸 磷酸二酯酶（PDE）和磷脂酶C（PLC）。由于这些化合物经历代谢，我们有 与6-姜烯酚代谢领域的世界专家合作，鉴定人体代谢物甚至新型合成物 保留增强的气道平滑肌作用效力的衍生物。我们还证明 6-姜烯酚的显著抗炎作用和抑制磷脂酶C信号通路， 巨噬细胞和淋巴细胞。因此，我们提出了一个统一的细胞信号转导机制的假设，如何6- 姜烯酚衍生物在变应性肺病中实现了这种双重益处：松弛气道平滑肌， 抗炎。在aim 1中，我们将继续我们对人体代谢物和新型合成衍生物的分析 的6-姜烯酚，以确定PLC和PDE抑制和平滑肌松弛的结构要求 同时鉴定出在人体上和下呼吸道中具有比母体6-姜烯酚化合物更大效力的衍生物 航空公司.在目标2中，我们将通过这些新的代谢产物和合成衍生物来证明其机制， 体外和小鼠精密切割肺中人巨噬细胞和CD 4+淋巴细胞活化受损 切片在目标3中，我们将结合这些机制发现并证明体内治疗潜力。急性 支气管扩张作用将通过小鼠肺和慢性抗- 将证明慢性屋尘螨抗原致敏期间的炎症作用。这些研究 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。

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.