The Severe Asthma Research Program III-Boston Clinical Site
The Severe Asthma Research Program III-Boston Clinical Site
Asthma is a disease characterized by inflammation in the airways. The body naturally makes
 compounds that reduce inflammation. Unfortunately, for patients with severe asthma, the
 pathway these compounds use to reduce inflammation seems to be perturbed. Investigators have
 chosen to focus on the anti-inflammatory compounds called lipoxins and how they work through
 the "ALX Axis", a name given to the ALX receptor pathway and its ligands. Work from the
 Brigham and Women's Hospital has suggested that in patients with severe asthma, the ALX axis
 may not work properly and therefore may not shut off inflammation as expected. Also, there is
 information to suggest that in some cases, steroids (prednisone and similar drugs), which are
 commonly used to treat asthma, may affect the ALX axis in a negative way, paradoxically
 making the inflammation worse instead of better.

 As part of the NIH Severe Asthma Research Program the Asthma Research Center's goal is to
 identify what causes the problems in the ALX axis in severe asthma. To do so, participants
 with severe asthma will be compared to participants with milder forms of asthma.
 Investigators will use samples taken directly from the lungs of people with asthma, as well
 as blood, urine and CT scans of the lungs to better understand how the ALX axis changes both
 before and after corticosteroid treatment and throughout a three year span. Participants will
 come into the Asthma Research Center to have the procedures done.

 Investigators expect participants will perform breathing tests and complete questionnaires
 and diaries. To better understand if corticosteroids negatively affect the ALX axis in severe
 asthma, researchers will take samples before and after a one time steroid injection
 equivalent to a prednisone treatment for asthma. Participants will perform two bronchoscopy
 procedures, before and after corticosteroid treatment, where biopsies and cells will be
 obtained from the participant's lungs. Investigators will use these samples to observe any
 changes that the corticosteroid may have on the ALX axis. At the end of the study,
 researchers at the Brigham and Women's Hospital expect to understand the ALX axis in such a
 way that will allow them to formulate new therapies and drug targets to treat people with
 asthma, especially severe asthma, more effectively.

 In Boston, this study will be run together by the Asthma Research Center at the Brigham and
 Women's Hospital (adults) and Boston Children's Hospital (children).
Severe asthma accounts for the majority of the morbidity and mortality related to asthma. It
 is characterized by persistent airway inflammation despite anti-inflammatory therapy,
 persistent airway hyperresponsiveness, and "remodeling" of the airways that includes
 fibrosis. Lipoxin A4 (LXA4) and 15-epimer-LXA4 are lipid-derived mediators that have been
 shown to promote anti-inflammatory and pro-resolving cellular responses through their effects
 at ALX/FPR2 receptors. They promote resolution of inflammation, inhibit airway
 hyperresponsiveness, and counteract pro-fibrotic processes. Investigators at the Brigham and
 Women's Hospital and others have shown that the ALX effector pathway and its constituent
 ligands (ALX axis) is perturbed in severe asthma (SA) compared with non-severe asthma (NSA).
 Specifically, in SA LXA4 production is decreased and ALX/FPR2 receptor expression is reduced.
 Further, investigators at the Brigham and Women's Hospital have shown that low levels of
 lipoxins, relative to pro phlogistic leukotrienes, are associated with reduced airway
 function (FEV1). Considering these data and the function of the ALX axis, it appears that
 perturbations of constituents of this axis could identify, and perhaps underlie, several of
 the processes that characterize severe, progressive asthma. Further to this point, work in
 progress being done at the Brigham and Women's Hospital indicates that corticosteroids (CS)
 interactions with the ALX axis may underlie some of these perturbations. CS can decrease the
 production of LXA4. More importantly, while CS increase production of pro-resolving annexin
 A1, they also appear to promote pro-inflammatory signaling through ALX/FPR2 via upregulation
 of serum amyloid A (SAA). SAA is expressed in the lung and is associated with exacerbations
 of COPD.

 Hypotheses:

 Peripheral blood leukocytes and bronchoalveolar lavage fluids will be obtained from SA and
 NSA subjects before and after intramuscular triamcinolone at baseline to test the hypothesis
 that in vivo corticosteroids will reduce pro-inflammatory cellular responses and enhance
 LXA4-mediated anti-inflammatory responses in the majority of asthmatic subjects. There is a
 sub-group of individuals with severe asthma in which in vivo corticosteroids will
 paradoxically increase pro-inflammatory responses. Investigators will also test the
 hypothesis that such paradoxical signaling can be overcome by lipoxins. In addition,
 investigators will test the hypothesis that basal p anti-inflammatory responses are dampened
 in severe asthma.

 Investigators at the Brigham and Women's Hospital hypothesize that a cohort of severe
 asthmatic subjects with impaired counter-regulatory signaling will have a specific ALX axis
 phenotype that will predispose them to increased inflammation, asthma exacerbations and
 disease progression.

 Investigators will test the hypothesis that in vivo corticosteroids will not increase (and
 may decrease) LXA4 or 15-epi-LXA4 but will increase annexin A1 and serum amyloid A and that
 the levels of these compounds post-CS will differ by disease severity, remaining stable over
 a 3 year interval.

 Samples will be obtained at study entry before and after intramuscular triamcinolone to test
 the hypothesis that in vivo corticosteroids increase ALX/FPR2 expression in leukocytes and
 airway cells.
Inclusion Criteria:

 -  Ages 6-60

 -  FEV1 bronchodilator reversibility ≥12% or methacholine PC20 ≤16 mg/mL

 -  Ability to provide informed consent

 -  Ability to perform pulmonary function tests

 Exclusion Criteria:

 -  Pregnancy (if undergoing methacholine challenge or bronchoscopy)

 -  Current smoking

 -  Smoking history > 10 pack years if ≥ 30 years of age or smoking history > 5 pack years
 if < 30 years of age (Note: If a subject has a smoking history, no smoking within the
 past year)

 -  Other chronic pulmonary disorders associated with asthma-like symptoms, including (but
 not limited to) cystic fibrosis, chronic obstructive pulmonary disease, chronic
 bronchitis, vocal cord dysfunction that is the sole cause of asthma symptoms, severe
 scoliosis or chest wall deformities that affect lung function, or congenital disorders
 of the lungs or airways

 -  Participants who cannot undergo bronchoscopy due to: 1) hospitalization for asthma
 within the 6 weeks prior to bronchoscopy, 2) > 12 asthma exacerbations within the 6
 months prior to bronchoscopy, 3) intubation for asthma within the 6 months prior to
 bronchoscopy, 4) older than 60 years of age, 5) increased corticosteroid use in the 14
 days prior to bronchoscopy. (Increased corticosteroid use recognized as a dose which
 is both numerically at least twice that of baseline, and which is at least 20 mg/day
 greater than the baseline dose.)

 -  History of premature birth before 35 weeks gestation

 -  Planning to relocate from the clinical center area before study completion

 -  Currently participating in an investigational drug trial

 -  Unwillingness to receive an intramuscular triamcinolone acetonide injection.