Fatty Acids in Airway Smooth Muscle of Asthmatics
Fatty Acids in Airway Smooth Muscle of Asthmatics
In this proof of concept study, the investigators aim to determine if supplementation with
 coconut oil causes an increase in cholecystokinin and cholecystokinin receptor expression in
 the airway smooth muscle of lean asthmatics, and whether these changes correlate with changes
 in airway stiffness (estimated by bronchodilator reversibility, airway reactivity, and airway
 resistance) or symptom control.

 The investigators propose a 5 week, single center trial in 20 lean patients with mild asthma
 (not taking inhaled corticosteroids) aged 18 and older. Subjects will supplement their usual
 diets with 3 tablespoons of coconut oil, a commercially available oil with high dodecanoic
 acid content, for 3 weeks. To quantify changes in airway smooth muscle cholecystokinin and
 cholecystokinin-receptor expression, each subject will undergo bronchoscopy with
 endobronchial biopsies before and after coconut oil ingestion.

 For the secondary analysis, subjects will also complete spirometry with bronchodilator
 testing, methacholine challenge, body plethysmography, and an Asthma Control Questionnaire
 (ACQ) before and after the dietary intervention. This information will be used to compare the
 changes in airway smooth muscle cholecystokinin and cholecystokinin receptor expression to
 changes in bronchodilator reversibility, airway reactivity, airway resistance, and symptom
 control.

 In the exploratory aims, the investigators will correlate the changes in airway smooth muscle
 cholecystokinin and cholecystokinin receptor expression with changes in FEV1 and peak flow
 measurements.

 The investigators therefore hope to elucidate information about the mechanistic role of
 cholecystokinin in airway smooth muscle stiffness and contraction.
20 lean (BMI<25) nonsmokers at least 18 years of age with mild asthma will be recruited from
 the Asthma Research Center database. A sample size of 12 asthmatics is needed to have 80%
 power to detect a 3-fold increase in cholecystokinin (CCK) post dodecanoic acid ingestion at
 alpha level of 0.05, assuming the standard deviation is ≤2.25 in cycle scale. To account for
 probable incomplete retention, 20 subjects will be recruited. While the calculated standard
 deviation is 1.775, the investigators chose to base our calculations off of a larger standard
 deviation because of our small sample size.

 Study subjects will be asked to come to 5 visits, described in detail below.

 Visit 1: Eligibility Screen Pre-screened Volunteers will be asked not to take their short
 acting bronchodilators or ipratropium within 6 hours of this visit. They will complete a
 medical history that includes detailed information about past and current asthma medications,
 ACQ, physical exam with weight/BMI check and spirometry with bronchodilator testing. They
 will undergo body plethysmography to measure baseline airway resistance.

 Visit 2: Eligibility Screen, methacholine challenge Subjects will return at any point during
 the 1-4 weeks allowed between visits 1 and 3. They will be told to not to take their short
 acting bronchodilators or ipratropium within 8 hours of this visit and to avoid caffeine
 (coffee, tea, cola drinks, and chocolate) the day of the visit. This visit will be short,
 comprised only of a methacholine challenge, to measure baseline airway reactivity.

 Visit 3: Bronchoscopy Eligible subjects will be asked not to take aspirin, anticoagulant
 (e.g., warfarin) or antiplatelet (e.g., clopidogrel) medication in the 7 days prior to this
 second visit. They will also be told not to eat or drink within 6hrs of the visit.

 At the beginning of the visit, subjects will be instructed on how to use a peak flow meter.
 Baseline peak flow measurements will be recorded. They will then undergo bronchoscopy with
 endobronchial biopsy. The investigators will perform laser capture on the biopsy samples to
 isolate the smooth muscle cells and quantify the cells' CCK and cholecystokinin receptor
 (CCK-AR) content via quantitative polymerase chain reaction (PCR).

 The study participants will then be instructed to supplement their usual diets with 3
 tablespoons of coconut oil (about 21.6g dodecanoic acid, 375 calories) daily for three weeks.
 The oil should be consumed uncooked so that its chemical form is unaltered. It can be
 swallowed by tablespoon or mixed into/spread on foods. The investigators recommend that it
 take the place of other fatty foods rather than be added to each subject's diet, so that
 subjects' overall daily caloric intake does not increase (and so that subjects do not gain
 weight).

 The average adult ingests 0.8g of dodecanoic acid daily, according to a 2004 NHANES report.
 Dodecanoic acid is present at particularly high concentration in coconut oil (50% dodecanoic
 acid by weight). While the degree to which ingested dodecanoic acid reaches plasma and airway
 smooth muscle cells is unknown, prior trials confirm rise in plasma concentration of similar
 fatty acids (including gama linolenic acid, stearidonic acid, alpha linolenic acid, and
 eicosapentaenoic acid) after supplementation with as little as 0.25-4g daily for 3 weeks. The
 investigators have chosen to maximize the supplemented dose (to about 20g) so that any
 possible effect of dodecanoic acid on the airway smooth muscle is not missed. The 3 week
 duration is modeled after the aforementioned studies.

 The investigators will provide each subject with a Drug Diary and peak flow meter. Subjects
 will be instructed to keep track of their daily coconut oil ingestion and peak flow
 measurements. They will be told to measure peak flow daily between 5 and 11 am, prior to the
 use of any morning inhalers, and to call the study coordinators if they experience a change
 in their asthma symptoms or if their measurements drop by more than 20% of their baseline. In
 addition, a study investigator will call each subject weekly to encourage compliance and to
 ensure that the subject has no questions or adverse events.

 Visit 4: Followup exam, ACQ, pulmonary function tests After 3 weeks of coconut oil ingestion,
 subjects will return for a repeat physical exam with weight/BMI check and methacholine
 challenge. They will fill out a second ACQ and continue to supplement their diet with coconut
 oil until visit 5.

 Visit 5: Followup pulmonary function tests, second bronchoscopy Subjects will return 1-3 days
 later for visit 5. They will again be told not to take aspirin, anticoagulant (e.g.,
 warfarin) or antiplatelet (e.g., clopidogrel) medication in the 7 days prior to this final
 visit, and not to eat or drink within 6hrs of the visit.

 The investigators will formally review each subject's Drug Diary and peak flow measurements.
 Eligible subjects will undergo spirometry, bronchodilator reversibility testing, body
 plethysmography, and bronchoscopy with endobronchial biopsy. The investigators will process
 the samples and compare the post-fatty acid ingestion outcomes to the baseline values.
Inclusion Criteria:

 1. Male and female participants, age 18 years and older at enrollment

 2. Never smokers or <10 pack year smoking history

 3. Body mass index (BMI) <25

 4. Clinical history consistent with asthma for >1 year

 5. No use of an inhaled corticosteroid in the prior 3mo

 6. Ability to perform reproducible spirometry according to ATS criteria

 7. Baseline Forced expiratory volume in 1 second (FEV1) ≥ 60% predicted

 8. Presence of bronchodilator reversibility, as defined by a minimum of 12% and ≥ 200 ml
 improvement after 4 puffs of albuterol, each 90 μg

 9. Ability to provide informed consent, as evidenced by signing a copy of the consent
 form approved by the Institutional Review Board.

 Exclusion Criteria:

 1. Supplementation with fatty acids within the last 3 months

 2. BMI ≥25

 3. Pregnant or nursing

 4. History of smoking (cigarettes, cigars, pipes, marijuana or any other substances)
 within the past 1 year, or >10 pack-years total

 5. Use of inhaled corticosteroid in the prior 3 mo

 6. Lack of bronchodilator response to 4 puffs of albuterol

 7. Medical contraindication to bronchoscopy/biopsy, i.e inability to stop aspirin,
 anticoagulant, or antiplatelet at any point during the study; coagulopathy; inability
 to lay flat; asthma exacerbation requiring corticosteroids in the preceding 4 weeks;
 history of adverse reaction or allergy to sedatives; history of difficult airway, or
 past difficulty with intubation

 8. Major medical problems prohibiting study participation, i.e presence of chronic or
 active lung disease other than asthma or history of unstable significant medical
 illness other than asthma

 9. Evidence that the participant may be non-adherent to medication regimen, or may move
 from the performance site area before trial completion