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

摘要 疾病控制中心报告称，2015年7.8%的美国人口患有哮喘， 非裔或拉丁裔血统的人(13.9%)或贫困线以下的人发病率较高 (11.1%)。几十年来，哮喘的维持治疗一直依赖吸入皮质类固醇和激动剂，但 近40%的哮喘患者的症状没有得到充分的控制。新兴的生物疗法与 针对IgE、细胞因子和细胞因子受体的抗体仅限于细微的表型 患者，是昂贵的，并且由于潜在的过敏反应，在卫生保健环境中需要每月给药。 此外，没有新的治疗类别的药物，急剧放松呼吸道平滑肌和 支气管收缩已经被引入了几十年。针对两个气道顺畅的新疗法 肌肉松弛和过敏性肺部炎症的减少将是巨大的临床益处。我们有 鉴定纯化的生姜天然成分，通过抑制两种受体而急性松弛呼吸道平滑肌 在平滑肌细胞功能中起关键作用的磷酸二酯酶家族；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了新陈代谢，我们已经 与6-shogaol代谢方面的世界专家合作，鉴定人类代谢物，甚至新的合成 保持增强的呼吸道平滑肌效应效力的衍生品。我们还展示了 6-shogaol的抗炎作用及对磷脂酶C信号通路的抑制作用 巨噬细胞和淋巴细胞。因此，我们提出了统一的细胞信号机制假说，即6- Shogaol衍生物在治疗过敏性肺部疾病方面实现了双重好处：松弛气道平滑肌和 消炎。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。 确定PLC和PDE抑制和平滑肌松弛的结构要求 同时在人体上下鉴定具有比母体6-shogaol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物和合成的衍生物来证明其作用机制。 小鼠肺精确切割术对人巨噬细胞和CD_4~+淋巴细胞体外和原位活化的影响 切片。在目标3中，我们将统一这些机制发现，并在体内展示治疗潜力。急性 在小鼠肺强迫振荡技术和慢性抗哮喘药物实验中，将证实其扩张支气管的作用。 将演示在慢性屋尘螨抗原致敏过程中的炎症效应。这些研究 将展示具有增强效力的新化合物的功能、机制和治疗潜力 针对哮喘的两个关键病理特征：呼吸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.