Mechanistic Insights From Bronchoscopy Airway Samples

The UCSF Airway Clinical Research Center has made longstanding and productive efforts to understand how type 2 immune responses in the airway act on epithelial cells to produce muco-obstructive pathology, a central feature of severe asthma and a major contributor to fatality from this disease. This center has made major contributions to identifying type 2 high asthma as the major asthma endotype, demonstrating that the type 2 cytokine IL-13 acts directly on airway epithelial cells to induce pathological changes in mucus, and showing that mucus plugging is a persistent feature of asthma that is associated with type 2 responses and with increased asthma severity. The overall objective of this proposal is to understand molecular mechanisms that account for alterations in secretory cell and mucus function that are important in severe asthma. The overarching hypothesis is that local type 2 immune responses induce IL-13-mediated changes in epithelial gene expression and that these changes, which involve several novel molecular mechanisms not previously explored, alter differentiation of secretory cells and production and secretion of mucins, leading to mucus plugging and airway obstruction. The proposal includes two highly related projects, each of which focuses on molecules and pathways that have previously unknown roles in secretory cell biology and mucus dysfunction. The proposed studies will provide new mechanistic insights that are highly relevant to the pathogenesis of severe asthma and may lead to novel therapeutic targets that address unmet needs.

Inclusion criteria

• Healthy Controls

• Male and female subjects between the ages of 18 and 70 years
• Ability to provide written informed consent and ability to comply with the requirements of the study
• No hyperreactivity to methacholine (PC20 FEV1 Methacholine >16 mg/mL)
• No history of allergic rhinitis/seasonal allergies
• Asthmatics

• Male and female subjects between the ages of 18 and 70 years
• Ability to provide written informed consent and ability to comply with the requirements of the study
• History of asthma
• No use of oral or inhaled corticosteroids for the treatment of asthma during the past 6 weeks
• Hyperreactivity to methacholine (PC20 FEV1 Methacholine < 8 mg/ml)

Exclusion criteria

The same exclusion criteria will apply to both Sub-studies.

• Current smokers, defined by (a) >5 cigarettes smoked in past 12 months, and (b) ≤ 8 weeks since last time smoking; or former smokers who have a total smoking history

• 10 pack-years
• Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study
• Subjects with a history of lung disease other than asthma
• Subjects with a history of prior esophageal hernia surgery
• Subjects with a history of a medical disease, which in the opinion of the Investigator may put the subject at extra risk from study-related procedures or because the disease may influence the results of the study
• Current participation in an investigational drug trial

Prohibited Medications and Treatments The following medications are prohibited during the study and must be discontinued prior to enrollment for the amount of time specified below.

• Astemizole: 12 weeks
• Steroids (oral, inhaled or nasal): 6 weeks
• Nedocromil sodium, sodium cromoglycate: 4 weeks
• Long-acting methylxantines: 2 days
• Short-acting methylxantines: 12 hours
• Montelukast: 7 days
• Zafirlukast: 7 days
• Salmeterol: 2 days
• Omalizumab: 6 months

Medications to be withheld prior to bronchoscopy: Aspirin or Non- steroidal anti-inflammatory agents (NSAIDs) for 2 days Medications to be withheld before each clinic visit: Short-acting bronchodilators (e.g. Albuterol) for 6 hours; Short-acting anti- cholinergics (e.g. Atrovent, Combivent) for 8 hours; and antihistamines (e.g. Benadryl, Claritin) for 3 days.