The Genetics of Environmental Asthma
Condition: Asthma
MeSH terms: Asthma
Study type: Interventional

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).
    

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.
    

Intervention name(s): LPS endotoxin, saline, HDM
Intervention type(s): Biological
Intervention description(s): instillation of interventional products during bronchoscopy each down a different airway, each subject acts as their own control.
Other intervention name(s): CCRE lipopolysaccharide endotoxin E.Coli O:113,Lot# 67801; House dust mite allergen (D.farinae) Greer Lab Lot #22574
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Genetics; Lipopolysaccharide