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

LIMA：哮喘中的脂质抗炎介质可减少肥胖哮喘患者的气道高反应性

• 批准号: 10369934
• 负责人: Stacy Lynn Gelhaus
• 金额: $ 74.16万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10369934
• 关键词: 16S ribosomal RNA sequencing; Acids; Adult; Airway Disease; Anti-Inflammatory Agents; Asthma; Basic Science; Biochemical; Biological; Biological Markers; Blinded; Body mass index; Bronchial Hyperreactivity; Bronchoalveolar Lavage; Bronchodilator Agents; Cells; Chronic; Clinical; Clinical Research; Cross-Over Studies; Crossover Design; Data; Disease; Drug Kinetics; Enzymes; Evaluation; Fatty Acids; Fatty acid glycerol esters; Feces; Functional disorder; Gene Expression; Gene Expression Profiling; Generations; Genome; Homologous Gene; Human; Immune response; Impact evaluation; Impairment; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Institutional Review Boards; Lipids; Lung; Mediating; Mediator of activation protein; Metabolic; Metabolic syndrome; Metabolism; Nasal Epithelium; Nitrogen Dioxide; Nitrogen Oxides; Nose; Obesity; Oral; Oral Administration; Oxidation-Reduction; Oxides; Oxygen; Pathogenicity; Patients; Pharmaceutical Preparations; Pharmacology; Phase II Clinical Trials; Phenotype; Placebo Control; Plasma; Population; Post-Translational Protein Processing; Publishing; Pulmonary Function Test/Forced Expiratory Volume 1; Pulmonary Inflammation; Questionnaires; Reaction; Research; Research Design; Resistance; Resources; Risk; Rodent; Safety; Sampling; Signal Transduction; Study Subject; Symptoms; Testing; Therapeutic Effect; Toxicology; Translational Research; Unsaturated Fatty Acids; Urine; Work; adipokines; airway hyperresponsiveness; allergic airway disease; asthmatic; asthmatic patient; bronchial epithelium; clinical phenotype; cytokine; design; drug candidate; dysbiosis; gut-lung axis; host microbiota; improved; insulin sensitivity; lipid mediator; metabolic profile; metabolomics; metatranscriptomics; methacholine; microbial; microbiome; mouse model; nitration; nitroalkene; novel; novel drug class; obese person; obesity treatment; obesity-associated asthma; phase 2 designs; phase 2 testing; pre-clinical; primary outcome; pulmonary function; receptor; response; secondary outcome; tool; transcription factor; transcriptome sequencing; volunteer; whole genome

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.

抽象的。肥胖会诱发慢性全身炎症状态，其特征是脂肪因子信号传导受损， 促炎细胞因子表达增加、炎症细胞活化、氧化生成增强 代谢中间体和微生物谱的物种和致病性变化。这会影响肺功能 并增加对传统哮喘治疗有抵抗力的哮喘及其恶化的发生率。 代谢和炎症反应产生的不饱和脂肪酸硝化产物（NO2-FA）可以 协调不同的自适应信号响应。当作为纯合成同系物施用时，NO2-FA 介导翻译后蛋白质修饰，调节多种酶、受体和 调节代谢和炎症的转录因子。口服合成NO2-FA 10-硝基- octadec-9-cis-enoic Acid（称为 NO2-OA 或 CXA-10）是一种安全、新型多效性候选药物， 内源性介质的合成同系物。在代谢综合征小鼠模型中，肥胖相关 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一新药类别的有前途的药理学 2 评估 CXA-10 对晚发性肥胖相关哮喘受试者的治疗效果。我们将 a) 定义每日服用支气管扩张剂前的 FEV1、哮喘控制和乙酰甲胆碱反应性的变化 通过盲法安慰剂对具有气道高反应性的肥胖受试者（BMI > 30）口服 CXA-10 对照、双交叉研究设计和 b) 评估 CXA-10 给药对研究对象的影响 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反应。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和 导致肥胖哮喘表型的炎症中间体。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 评估了以下药物的临床反应： 肥胖相关哮喘患者口服硝基脂肪酸、CXA-10 和目标 #2 识别下游宿主和微生物基因表达以及受试者的代谢反应 口服 CXA-10 给药前后。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，从而有益地影响肠肺轴。