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.

摘要。肥胖诱导慢性全身性炎症状态，其特征是脂肪因子信号受损，