LIMA: Lipid anti-Inflammatory Mediators in Asthma to reduce airway hyperresponsiveness in obese asthmatics

抽象的。肥胖诱导以脂肪因子信号传导受损为特征的慢性全身性炎症状态， 促炎细胞因子表达增加，炎性细胞活化，氧化性细胞因子生成增加， 代谢中间体和微生物谱的种属和致病性变化。这会影响肺功能 并且增加了对常规哮喘治疗有抗性的哮喘及其恶化的发病率。 代谢和炎症反应产生的不饱和脂肪酸硝化产物（NO2-FA）， 协调不同的适应性信号反应。当作为纯合成同系物给药时，NO2-FA 介导翻译后蛋白质修饰，其调节多种酶、受体和 调节代谢和炎症的转录因子。口服合成的NO2-FA 10-硝基- 十八碳-9-顺式-烯酸（称为NO2-OA或CXA-10）是一种安全的新型多效性候选药物， 内源性介质的合成同系物。在代谢综合征的鼠模型中，肥胖相关的 过敏性气道疾病和肺部炎症证实CXA-10诱导抗炎反应 并使气道功能正常化。我们将通过阶段评估这种新药类别的有前途的药理学 2 CXA-10治疗晚发性肥胖相关性哮喘的疗效评价。我们将 a）定义每日给药后使用支气管扩张剂前FEV 1、哮喘控制和乙酰甲胆碱反应性的变化 口服CXA-10给药于具有气道高反应性的肥胖受试者（BMI >30），通过盲法、安慰剂- 对照、双交叉研究设计和B）评价CXA-10给药对研究受试者的影响 鼻和肺气道细胞基因表达，尿液、血浆和支气管肺泡灌洗液炎症 生物标志物和肠-肺轴微生物组响应。这些机制研究将揭示CXA-10如何指导 亲电NO2-FA敏感基因组和微生物组调节全身和气道代谢， 导致肥胖哮喘表型的炎性中间体。我们假设硝基脂肪 酸诱导的信号传导和代谢反应将改善肺功能，哮喘控制和缓解 肥胖相关的气道高反应性。为了检验这一假设，目标1评价了以下患者的临床反应： 肥胖相关哮喘患者口服硝基脂肪酸、CXA-10和Aim #2 鉴定受试者的下游宿主和微生物基因表达和代谢反应 在口服CXA-10之前和之后。目前的数据表明，在肥胖的情况下，CXA-10 将限制肺功能障碍，促进适应性信号反应并改变肠道细菌种群和代谢 中间体，以便有利地影响肠-肺轴。

Abstract. Obesity induces a chronic systemic inflammatory state characterized by impaired adipokine signaling, increased pro-inflammatory cytokine expression, inflammatory cell activation, enhanced generation of oxidizing species and pathogenic shifts in metabolic intermediates and microbial profiles. This impacts pulmonary function and increases the incidence of asthma and its exacerbations that are resistant to conventional asthma therapies. Unsaturated fatty acid nitration products (NO2-FA), generated by metabolic and inflammatory reactions, can orchestrate diverse adaptive signaling responses. When administered as pure synthetic homologs, NO2-FA mediate post-translational protein modifications that modulate activities of multiple enzymes, receptors and transcription factors regulating metabolism and inflammation. Oral administration of synthetic NO2-FA 10-nitro- octadec-9-cis-enoic acid (termed NO2-OA or CXA-10) is a safe, novel pleiotropic drug candidate that is a synthetic homolog of an endogenous mediator. In murine models of metabolic syndrome, obesity-associated allergic airway disease and pulmonary inflammation affirms that CXA-10 induces anti-inflammatory responses and normalizes airway function. We will evaluate the promising pharmacology of this new drug class via Phase 2 evaluation of the therapeutic effects of CXA-10 in subjects with late onset obesity-associated asthma. We will a) define changes in pre bronchodilator FEV1, asthma control, and methacholine responsiveness following daily oral CXA-10 administration to obese subjects (BMI >30) having airway hyperreactivity, via a blinded, placebo- controlled, double cross-over study design and b) evaluate the impact of CXA-10 administration on study subject nasal and pulmonary airway cell gene expression, urine, plasma and bronchoalveolar lavage inflammatory biomarkers and gut-lung axis microbiome responses. These mechanistic studies will reveal how CXA-10 directs the electrophilic NO2-FA-sensitive genome and microbiome to modulate systemic and airway metabolic and inflammatory intermediates that contribute to the obese asthmatic phenotype. We hypothesize that nitro-fatty acid-induced signaling and metabolic responses will improve lung function, asthma control and alleviate obesity-related airway hyperreactivity. To test this hypothesis, Aim #1 evaluates the clinical responses of obesity-associated asthma patients to the orally-administered nitro-fatty acid, CXA-10 and Aim #2 identifies the downstream host and microbial gene expression and metabolic responses of subjects before and after oral CXA-10 administration. Current data encourages that, in the setting of obesity, CXA-10 will limit lung dysfunction, promote adaptive signaling responses and shift gut bacterial populations and metabolic intermediates so as to beneficially impact the gut-lung axis.