Nitric Oxide, LPS and the Pathogenesis of Asthma - Phase II
Trial Snapshot
- Phase
- Phase 1
- Status
- Terminated
- Sponsor
- Enrollment
- 70
- Locations
- 2
- Primary Endpoint
- Differential response to inhaled LPS based on NOS2 inhibition.
Study Overview
Brief Summary
The purpose of the study is to determine the role of nitric oxide (NO) in asthma and to characterize the symptoms associated with inhaled endotoxin (lipopolysaccharide [LPS]) in normal subjects. In this study, we will determine the effect of inhaled endotoxin on exhaled NO in healthy African Americans, with and without NOS2 promoter polymorphisms. The protocol described in this submission will involve the use of NIH Clinical Center Reference Endotoxin which has been approved by the FDA under IND BB-IND-10035.
Detailed Description
(IRB# Pro00005035)
The purpose of the study is to determine the role of nitric oxide (NO) in asthma and to characterize the symptoms associated with inhaled endotoxin in normal subjects. The effect of inhaled endotoxin on exhaled NO is determined in healthy African Americans, with and without NOS2 promoter polymorphisms. The protocol involves the use of NIH Clinical Center Reference Endotoxin which has been approved by the FDA under IND BB-IND-10035.
Background & significance: Asthma is a significant cause of morbidity and mortality for African Americans and asthma is increasing in prevalence. Both environmental and genetic factors contribute to the pathogenesis of asthma. In addition to allergens, environmental lipopolysaccharide (LPS) or endotoxin plays an important role in the chronic inflammation associated with asthma. There is convincing evidence that endotoxin exacerbates airflow obstruction and airway inflammation in allergic asthmatics. Endotoxin increases inducible nitric oxide synthase (NOS2) expression and nitric oxide (NO) production in vitro and in vivo in humans.
In asthma, NOS2 expression is upregulated in several cell types including bronchial epithelium, macrophages and other inflammatory cells. The increase in NOS2 expression is associated with increases in exhaled NO in individuals with asthma as compared to healthy individuals.
This prompted our search for NOS2 single nucleotide polymorphisms (SNPs) and the subsequent identification of three NOS2 promoter SNPs. Two of the SNPs are associated with increased systemic NO levels. Another SNP creates a predicted binding site for the human homolog of delta EF1, which is a transcriptional repressor and we predicted that this SNP would be associated with low NO levels. Importantly, the three NOS2 promoter SNPs are not linked, do not segregate together and are present primarily in individuals of African ancestry.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Basic Science
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 40 Years (Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •Willing/able to give informed consent & adhere to visit/protocol schedules
- •non-atopic, non-asthmatic by PFT and allergy skin testing
- •never cigarette smoker,
- •no significant occupational exposure to respiratory irritants or toxins,
- •no chronic illness
- •no chronic use of medications (excluding contraceptive medication),
- •no systemic corticosteroid use in the previous month,
- •no historical or physical examination evidence of unstable cardiac or severe lung disease,
- •Women of childbearing potential must have a negative serum pregnancy test
- •baseline FEV1 > 80% of the predicted value,
- •no clinically significant abnormalities on the chest x-ray or EKG
Exclusion Criteria
- •occupational exposure to hay or grain
- •smoked 20 or more packs of cigarettes in a lifetime.
- •prior allergen immunotherapy
- •Allergy to potential study medications acetaminophen and albuterol
- •Subjects who abuse alcohol or illicit substances will be excluded
- •Viral respiratory infection within the previous 14 days
- •Students or employees under direct supervision by protocol investigators are ineligible
- •Nursing mothers
- •Other investigational medication within the last 30 days
- •Other medical or psychological conditions which, in the opinion of the investigator, might create undue risk to the subject or interfere with the subject's ability to comply with the protocol requirements
Outcomes
Primary Outcomes
Differential response to inhaled LPS based on NOS2 inhibition.
Time Frame: 24 hours with optional 48 hr,72hr and 7 day follow up
Secondary Outcomes
- Physiologic measurements(24 hours with optional return up at 48 hrs, 72hrs and 7 day follow up)
Investigators
John Sundy
Associate Professor of Medicine
Duke University