Study of the Mechanisms of Asthma

Asthma is a common airway disease with persistent unmet needs on terms of treatment. Although many asthmatics enjoy good control of their disease by using regularly scheduled corticosteroid treatment, a significant minority do not achieve optimal control with steroids and suffer asthma exacerbations which can be severe and even fatal. Asthma pathophysiology is complex and involves multiple cell types and multiple signaling mechanisms. One approach to this complexity has been to study responses of isolated airway cells to experimental conditions which model asthmatic inflammation; another has been genetic manipulations of candidate mediators of asthma in inbred mice. These studies have yielded important insights about possible mechanisms of asthma in humans, but the relevance of these mechanisms to human disease has not always been proven, and it is possible that unsuspected mechanism have not yet been revealed by these approaches. In the studies proposed here we will take an experimental approach which takes advantage of the distinct clinical phenotype of human asthma, the ability to measure steroid response in asthma, the relative ease of collecting airway cells and tissues by bronchoscopy, and the availability of new technologies such as high density microarrays which have probes for all genes in the genome or proteomics which can identify all proteins present in a biologic sample. Using this approach, we will identify differential expression of genes and proteins in airway cells and tissues in asthma that can then be explored further in cell and animal model systems to determine their potential as drug targets in asthma. We further believe that our approach will identify previously unsuspected mechanisms of action of corticosteroids in airway cells and tissues in asthma. Presently, relatively little is known about why some asthmatics respond well and some poorly to steroids and closing this gap in knowledge will help identify candidate genes and proteins to target in order to address unmet therapeutic needs in asthmatics with steroid resistant asthma.

Inclusion criteria

Group C:

• Male and female subjects between the ages of 18 and 70 years
• History of asthma
• Continuous treatment with inhaled corticosteroids for at least the 6-week
• Hyperreactivity to methacholine (provocative concentration of methacholine causing a 20% drop in forced expiratory volume in 1 second (PC20 FEV1) Methacholine ≤ 16.0 mg/mL).

Exclusion criteria

• History of asthma
• No use of oral or inhaled corticosteroids for the treatment of asthma in the past 6 weeks
• Hyperreactivity to methacholine (PC20 FEV1 Methacholine ≤ 8.0 mg/mL).
• At least one of the following symptoms, beta agonist use, or FEV1 criteria:

• Asthma symptoms on at least two days per week; OR
• Beta agonist use on at least two days per week; OR
• Forced expiratory volume in 1 second (FEV1) < 85% predicted
• Subjects must be non-smokers (patients who have never smoked or patients who have not smoked for 1 year and have a total pack-year smoking history < 15 packs).