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Eicosanoid Lipids by Airway Cells During Infection With Human Rhinoviruses

2019年3月27日 更新者:University of Wisconsin, Madison

Production of Eicosanoid Lipids by Airway Cells During Infection With Human Rhinoviruses: An In Vitro Model System to Study the Mechanisms of Asthma Exacerbation Resolution

The long-range goal of this protocol is to more completely understand the risks and the pathophysiology of asthma exacerbations, in order to develop prevention strategies and/or expedite a return to complete control of baseline asthma symptoms.

研究概览

地位

完全的

条件

详细说明

Theinvestigators and others have shown that airway epithelial cell infection with human rhinovirus (HRV) is a major risk factor for subsequent exacerbation. Additionally, the investigators have shown that the nucleotide receptor, P2X7, is an important host factor in the prevention of exacerbations, and have data to suggest that this may occur at the level of the alveolar macrophage. Alveolar macrophages facilitate the resolution of inflammation in part by generating eicosanoid metabolites of arachidonic acid including prostaglandin E2 (PGE2) and lipoxin A4 (LXA4). Patients with severe asthma have a reduced capacity to generate PGE2 and LXA4 when compared to those with non-severe asthma, despite alveolar macrophage expression of two of the key enzymes involved in their production. These and other data suggest that pro-resolving eicosanoid metabolism is most efficient when airway epithelial cells are in communication with alveolar macrophages, and that these pathways may be defective in patients with severe asthma. Moreover, inoculation experiments with human rhinovirus (HRV) demonstrate that alveolar macrophages express cox-2 during resolution. These and other data have led to the central hypothesis that transcellular generation of PGE2 and lipoxins is regulated by P2X7-induced cox-2 expression in alveolar macrophages, and that this process facilitates resolution of an HRV-triggered exacerbation.

研究类型

观察性的

注册 (实际的)

44

联系人和位置

本节提供了进行研究的人员的详细联系信息,以及有关进行该研究的地点的信息。

学习地点

    • Wisconsin
      • Madison、Wisconsin、美国、53792
        • UW Madison

参与标准

研究人员寻找符合特定描述的人,称为资格标准。这些标准的一些例子是一个人的一般健康状况或先前的治疗。

资格标准

适合学习的年龄

18年 至 55年 (成人)

接受健康志愿者

有资格学习的性别

全部

取样方法

非概率样本

研究人群

Subjects with mild asthma from Madison, WI region

描述

Inclusion Criteria:

  • Age 18-55 years
  • Diagnosis of mild asthma
  • Pre-albuterol forced expiratory volume in the first second (FEV1) of >70% predicted.
  • Confirmation of asthma diagnosis by either an improvement in FEV1 after four puffs of albuterol by ≥ 12%, or a decline in FEV1 by ≥ 20% after a graded challenge with inhaled methacholine with a provocative concentration causing a 20% fall ≤ 8 mg/mL
  • Documented negative Tuberculin skin test (PPD) within the last 12 months or a medical history that is consistent with a low probability of exposure to tuberculosis (i.e. the subject is not a health worker, has not traveled to endemic areas, and has no pre-existing medical or social risk factors for tuberculosis).
  • Safety laboratory assessments within normal ranges (labs to include complete blood count with differential and platelet count, PT/INR, creatinine, ALT)
  • Women of child-bearing potential (WCBP) must have a negative urine pregnancy test (urine HCG) within 48 hours of the methacholine challenge at Visit 2, within 48 hours of the bronchoscopy at Visit 3 and within 48 hrs of Visit 4. WCBP must agree to use a reliable method of birth control for the duration of the study (reliable methods of birth control can include abstinence, barrier methods, oral contraceptives, injection contraceptives or skin absorption contraceptives).
  • In the opinion of the investigator, capable and willing to grant written informed consent and cooperate with study procedures and requirements.

Exclusion Criteria:

  • Major health problems such as autoimmune disease, heart disease, type I and II diabetes, uncontrolled hypertension or lung diseases other than asthma. The listed health problems are definitive exclusion but decisions regarding major health problems not listed will be based upon the judgment of the investigator.
  • No pre-existing chronic infectious disease.
  • Any condition for which, in the opinion of the investigator, transient oxyhemoglobin desaturation is inadvisable.
  • Pregnant or lactating females or has a planned pregnancy during the course of the study.
  • Asthma maintenance therapy other than inhaled short acting beta-agonists within 1 month of screening. This includes but is not limited to inhaled or oral corticosteroids, long acting beta-agonists and leukotriene receptor antagonists.
  • Upper or lower respiratory infection within 1 month of screening.
  • Unstable asthma as indicated by self-report of increased symptoms or increased beta-agonist use over the 2 weeks preceding the screening visit.
  • Current smokers (defined as smoked within the last year) or a former smoker with a history of >10 pack years.
  • Morbid obesity as defined by a Body Mass Index (BMI) > 40.
  • Use of an investigational drug within 30 days of entering the study
  • History of noncompliance with medical regiments or subjects who are considered unreliable including those with a psychiatric history that, in the opinion of the investigator, may interfere with the conduct of study procedures.

学习计划

本节提供研究计划的详细信息,包括研究的设计方式和研究的衡量标准。

研究是如何设计的?

设计细节

队列和干预

团体/队列
Mild asthma
Diagnosis of mild asthma as defined by pre-albuterol forced expiratory volume in the first second (FEV1) of >70% predicted.

研究衡量的是什么?

主要结果指标

结果测量
措施说明
大体时间
Cox2 expression
大体时间:One day
P2X7 agonist-induced fold stimulation (over the media control) of cox2 expression (assessed by densitometry) in alveolar macrophages primed with conditioned medium from minor group HRV-infected epithelial cells.
One day
BzATP-induced PGE2
大体时间:One day
The amount of BzATP-induced PGE2 in the culture supernatants of alveolar macrophages primed with HRV-infected epithelial conditioned media
One day
LXA4 produced by BzATP
大体时间:One day
The amount of LXA4 produced by BzATP co-treatment of HRV infected of epithelial-macrophage co-cultures.
One day

合作者和调查者

在这里您可以找到参与这项研究的人员和组织。

调查人员

  • 首席研究员:Loren Denlinger, MD/PhD、UW Madison

研究记录日期

这些日期跟踪向 ClinicalTrials.gov 提交研究记录和摘要结果的进度。研究记录和报告的结果由国家医学图书馆 (NLM) 审查,以确保它们在发布到公共网站之前符合特定的质量控制标准。

研究主要日期

学习开始 (实际的)

2013年12月17日

初级完成 (实际的)

2017年8月29日

研究完成 (实际的)

2017年8月29日

研究注册日期

首次提交

2013年7月9日

首先提交符合 QC 标准的

2013年7月11日

首次发布 (估计)

2013年7月12日

研究记录更新

最后更新发布 (实际的)

2019年3月28日

上次提交的符合 QC 标准的更新

2019年3月27日

最后验证

2019年3月1日

更多信息

与本研究相关的术语

其他研究编号

  • 2013-0935
  • 1R01HL115118-01A1 (美国 NIH 拨款/合同)

计划个人参与者数据 (IPD)

计划共享个人参与者数据 (IPD)?

是的

此信息直接从 clinicaltrials.gov 网站检索,没有任何更改。如果您有任何更改、删除或更新研究详细信息的请求,请联系 register@clinicaltrials.gov. clinicaltrials.gov 上实施更改,我们的网站上也会自动更新.

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