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The Genetics of Environmental Asthma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00018096
Recruitment Status : Completed
First Posted : July 4, 2001
Last Update Posted : May 6, 2008
National Center for Research Resources (NCRR)
Information provided by:
National Institute of Environmental Health Sciences (NIEHS)

Brief Summary:
In this project, we hypothesize that polymorphisms of genes expressed by the airway epithelia in asthmatics following specific airway challenges predispose individuals to the development of asthma. To test this hypothesis, we identify the genes that are differentially expressed by airway epithelial cells following challenge with stimuli that induce acquired (house dust mite) or innate (LPS) immune responses, and then determine whether polymorphisms in these genes are associated with the development of asthma in a separate, well characterized, familial cohort of asthmatics. This is a powerful approach that is designed to identify novel genes that are associated with both asthma pathogenesis (differentially expressed in the exposure-response study) and asthma susceptibility (genetically associated with asthma in a linkage/association study).

Condition or disease Intervention/treatment Phase
Asthma Biological: LPS endotoxin, saline, HDM Not Applicable

Detailed Description:
The overall goal of this project is to identify genes that are involved in the development of airflow obstruction and airway inflammation in asthmatics, and to determine whether polymorphisms in these differentially expressed genes predispose individuals to develop asthma. Asthma is a complex genetic disorder that is caused by a number of unique gene-gene and gene-environment interactions. The search for asthma susceptibility genes has been complicated by the broad clinical phenotype of asthma, the polygenic inheritance pattern of this disease, and the substantial role of environmental exposures in the development and progression of asthma. Inhaled environmental agents induce several biologic responses in asthmatics; including the induction of acquired and innate immunity that leads to acute and chronic forms of airway inflammation and airway remodeling. Acquired immune responses to protein antigens, such as house dust mite allergen, often induce type 2 T lymphocyte-driven responses (Th2) which appear to be important in atopic asthma. Recent studies by our group and others demonstrate that innate immunity, initiated by inhalation of bacterial and viral pathogens, organic dusts, endotoxin or lipopolysaccharide (LPS), air pollution particulate matter, and ozone, can also cause acute and chronic forms of airflow obstruction, airway inflammation, and even airway remodeling. Emerging evidence indicates that both acquired and innate immune responses in the lung may be influenced by polymorphic genes. For instance, functional polymorphisms in the IL-4 receptor gene are thought to preferentially stimulate acquired Th2 immune responses to inhaled allergens, and we have recently shown that common co-segregating mutations in TLR4 (a transmembrane receptor for LPS) are associated with diminished airway responsiveness to inhaled LPS. These observations suggest that environmental challenges can be used to narrow the phenotype of asthma and investigate genetic susceptibility in biologically specific forms of asthma.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 176 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: The Genetics of Environmental Asthma
Study Start Date : June 2001
Actual Primary Completion Date : December 2007
Actual Study Completion Date : December 2007

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Asthma

Arm Intervention/treatment
Experimental: bronchoscopy
2 bronchoscopies 4 hours apart; The first to instill the 3 experimental biologic agents in separate airways (HDM, LPS and saline-placebo), the second to perform BAL and brush biopsies 4 hours later in the same airways.
Biological: LPS endotoxin, saline, HDM
instillation of interventional products during bronchoscopy each down a different airway, each subject acts as their own control.
Other Names:
  • CCRE lipopolysaccharide endotoxin E.Coli O:113,Lot# 67801
  • House dust mite allergen (D.farinae) Greer Lab Lot #22574

Primary Outcome Measures :
  1. BAL and endobronchial brush biopsy are measured and cell samples are analyzed to identify the genes in airway epithelia and inflammatory cells that are differentially expressed in response to LPS and dust mite antigen.RNA is isolated for gene expression. [ Time Frame: 4 hours post first instillation bronchoscopy ]

Secondary Outcome Measures :
  1. post bronchoscopy symptom followup [ Time Frame: 48 hours ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • Atopic/asthmatic, atopic/non-asthmatic, non-atopic/asthmatic, or non-atopic/non-asthmatic
  • Asthma subjects will be required to have either mild or moderate persistent asthma; positive methacholine challenge
  • Atopic subjects should have seasonal allergy symptoms requiring medication and have positive skin test to house dust mite and at least 3 additional allergens. Serum IgE level >100.
  • Willing/able to give informed consent & adhere to visit/protocol schedules.
  • Screening visit laboratory, C-Xray, EKG, results within normal limits
  • Women of childbearing potential must have a negative serum pregnancy test
  • Screening Pulmonary Function testing above study criteria parameters

Exclusion Criteria:

  • Systemic corticosteroid administration for asthma within the previous 90days
  • Antibiotic administration within the previous 30 days.
  • Viral respiratory infection within the previous 14 days.
  • History of severe asthma requiring intubation.
  • Occupational exposure to hay or grain dust.
  • Significant exposure history to cigarette smoke
  • Past or present history of allergen immunotherapy
  • Underlying illnesses that may result in altered lung function
  • Students or employees under direct supervision by protocol investigators are ineligible
  • Subjects allergic to medications used (or potentially used) in the study will be excluded.
  • Subjects using aspirin will be excluded
  • Subjects who abuse alcohol or illicit substances will be excluded
  • Medication use other than for asthma, allergies or contraception
  • 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
  • Nursing mothers
  • Other investigational medication within the last 30 days

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00018096

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United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
Sponsors and Collaborators
National Institute of Environmental Health Sciences (NIEHS)
National Center for Research Resources (NCRR)
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Principal Investigator: Sundy S. Sundy, MD. PhD. Duke University

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Responsible Party: John S. Sundy M.D., PhD., Duke University Medical Center Identifier: NCT00018096     History of Changes
Other Study ID Numbers: NCRR-M01RR00030-0183
First Posted: July 4, 2001    Key Record Dates
Last Update Posted: May 6, 2008
Last Verified: May 2008
Keywords provided by National Institute of Environmental Health Sciences (NIEHS):
Additional relevant MeSH terms:
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Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Respiratory Hypersensitivity
Hypersensitivity, Immediate
Immune System Diseases