Purpose: To determine if inhaled hypertonic saline (HS) accelerates airway mucociliary clearance (MCC) in well-controlled moderate to severe asthmatics.

Participants: Non-smoking adults with well controlled moderate to severe asthma

Procedures (methods): After undergoing a general health screen, participants will undergo a lung transmission scan to create an image of the lungs. In subsequent visits, participants will inhale nebulized radiolabeled aerosol and sit in front of a gamma camera for 2 hours to measure clearance of radiolabeled particles from the lungs (procedure called gamma scintigraphy), which will be used to calculate baseline MCC. Spirometry will be performed before and at regular intervals after HS to assess for clinically significant reductions in lung function. Vital signs and symptom questionnaires will be administered as well. If participants are deemed tolerant to HS (i.e., no clinically significant deterioration in lung function, vital signs, or symptom questionnaire scores), participants will move forward with study visits.

Inclusion Criteria:

• Age 18-60 of both genders-
• Moderate to severe asthma at baseline (determined by Step 3 therapy or greater or by asthma impairment) and well-controlled asthma at the time of enrollment, as determined by NHLBI Expert Panel Report 3 guidelines for diagnosis and treatment of asthma.
• Negative pregnancy test for females who are not s/p hysterectomy with oophorectomy.
• Forced expiratory volume in 1 sec (FEV1) of at least 70% of predicted for age, sex, height, and race/ethnicity (without use of bronchodilating medications for 12 hours or long acting beta agonists for 24 hours).
• Documented COVID-19 vaccination

Exclusion Criteria:

Subjects who meet any of these criteria are not eligible for enrollment as study participants:

1. Clinical Contraindications:

   Any chronic medical condition considered by the PI as a contraindication to the study including significant cardiovascular disease, diabetes, chronic renal disease, chronic thyroid disease, history of chronic infections/immunodeficiency, or history of tuberculosis Any acute infection requiring antibiotics within 4 weeks of study. Mental illness or history of drug or alcohol abuse that, in the opinion of the investigator, would interfere with the participant's ability to comply with study requirements.

   Medications which may impact the results of the study treatment, or may interfere with any other medications potentially used in the study (to include steroids, beta antagonists, non-steroidal anti-inflammatory agents) Active smoking to include e-cigarettes within 1 year of the study, or lifetime of > 10 pack-years of smoking Allergy/sensitivity to study drugs, or their formulations. History of intubation for asthma Unwillingness to use reliable contraception if sexually active (birth control pills/patch, condoms).

   Viral upper respiratory tract infection within 4 weeks of challenge. Radiation exposure history in the past year that would cause the participant to exceed Federal radiation safety guidelines.

2. Pregnant women and children (< 18 years as this is age of majority in NC) will also be excluded since the risks associated with hypertonic saline inhalation to the fetus or child and the risk of radiation are unknown and cannot be justified.

3. Use of the following medications:

   1. Systemic corticosteroids; subjects with systemic corticosteroid-dependent asthma will be excluded. All use of systemic steroids in the last year will be reviewed by a study physician.
   2. Use of daily theophylline within the past month
   3. Use of any immunosuppressant/immunomodulatory therapy within the preceding 12 months
   4. Use of beta blocking medications
   5. Receipt of Live Attenuated Influenza Vaccine (LAIV), also known as FluMist®, within the prior 30 days, or any vaccine within the prior 5 days
   6. Multivitamins, Vitamin C or E or herbal medications in the 4 days prior to the treatment visit
   7. Non-steroidal anti-inflammatory drugs in the 4 days prior to the treatment visit
   8. Subjects must be able to withhold morning doses of maintenance inhalers on the treatment days, including long acting bronchodilators and inhaled corticosteroids.
   9. Positive COVID-19 test in the prior 90 days.

4. Allergy/sensitivity to study drugs or their formulations: Known Immunoglobulin E (IgE) -mediated hypersensitivity to albuterol, diphenhydramine or corticosteroids.

5. Physical/laboratory indications:

   1. Abnormalities on lung auscultation
   2. Temperature > 37.8
   3. Systolic BP >150 mm Hg or < 90 mm Hg or diastolic BP> 90 mm Hg or < 50
   4. Oxygen saturation of < 93%

6. Inability or unwillingness of a participant to give written informed consent.

From the time of signing informed consent through study completion, up to approximately 3.5 months