Nasal Endotoxin Challenge to Study Mucosal Inflammation in Patients With Asthma
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Neutrophil heterogeneity using single cell RNA sequencing
研究概览
简要总结
A phase I clinical research study aimed at determining mechanisms that regulate airway mucosal inflammation in asthma endotypes using intranasal administration of endotoxin (lipopolysaccharide from E. coli) in healthy controls and subjects diagnosed with asthma.
详细描述
Patients with severe asthma can be broadly classified into three endotypes (T2, T1, and T17) based on inflammatory cell and cytokine profiles. Within these endotypes, many patients have high levels of neutrophils in the airways and mucosal epithelium. Our preliminary data suggest that neutrophils in the airways and blood of patients with severe asthma are heterogenous and that subsets exist. The nature of these subsets appears to differ between T2, T1, and T17 asthma endotypes.
In order to advance the field and determine the mechanisms that underpin severe neutrophilic asthma, investigators plan to longitudinally assess transcriptional profiles and functional properties of neutrophil subsets that migrate to the nasal cavity following exposure to a standardized dose of Clinical Reference Center endotoxin (IRB#HS-3131-528, IND 018580).
Investigators will recruit 15 subjects of each asthma endotype (45 total participants with asthma) and 15 healthy controls. LPS will be used to elicit migration of neutrophils into the nasal cavities. Neutrophils will be isolated from the nasal cavities using both nasal lavage and nasal brushes 20 minutes, 1 day and 3 days after endotoxin challenge. Neutrophil biology will be assessed using single-cell RNAseq and ex vivo functional assays.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Participants will have asthma diagnosed by a health care provider. Healthy controls are individuals without asthma.
- •Written informed consent
排除标准
- •Current or recent illness (in the past 4 weeks)
- •Recent asthma exacerbation (past 4 weeks)
- •History of nasal perforation or nasal surgery
- •Nasal polyposis
- •Presence or prior history of cardiac or systemic disease
- •Bleeding disorder, use of systemic anticoagulants, or antiplatelet therapy
- •Immunocompromised state (HIV, immunoglobulin deficiency, systemic immunosuppressants excluding corticosteroids)
- •Use of tobacco or marijuana in the past 2 months or greater than a 10 pack-year smoking history
- •Currently pregnant or breastfeeding
研究组 & 干预措施
Asthma Group
Subjects diagnosed with one of the three asthma endotypes being studied (T2, T1, or T17).
干预措施: Lipopolysaccharides (Drug)
Control Group
Subjects with no diagnosis of asthma or other respiratory disease and are deemed healthy.
干预措施: Lipopolysaccharides (Drug)
结局指标
主要结局
Neutrophil heterogeneity using single cell RNA sequencing
时间窗: We anticipate that the study will run over 5 years
Neutrophil subset composition as determined by single cell RNAseq is compared to endotype groups using a multivariate linear regression framework for compositional data, employing the additive log ratio transformation. Models will include indicator variables for whether a sample is T1 high, T2 high, T17 high or non-asthmatic and will control for age, sex, and smoking status. AM subset gene expression matrices from scRNAseq will be compared between endotypes using the pseudo bulk approach to account for clustering of cells within subjects. To identify global gene expression programs underlying each endotype, bulk RNAseq gene expression data will be normalized using DESeq2's variance stabilizing transformation and similarly compared between endotypes using linear regression models. A Benjamini-Hochberg adjustment will be used to control the false discovery rate.
次要结局
未报告次要终点
研究者
William Janssen, MD
Section Head of Critical Care, Professor of Medicine, Principle Investigator
National Jewish Health