Oxidative Stress in Asthma
Oxidative Stress in Asthma
40% of all asthma patients in the US are obese. Obese asthmatics have more severe disease
 than lean asthmatics and do not respond as well to conventional anti-inflammatory therapies.
 This proposal will utilize 3D functional imaging with 129XeMRI and single cell RNA sequencing
 to study mechanisms driving regional airway remodeling and fibrosis in obese asthma subjects
 and in preclinical models of obese asthma.
ABSTRACT

 Obesity, a major comorbidity and a potential modulator of asthma, affects nearly 40% of
 asthmatics in the U.S., and increases its severity. Obese asthmatics do not respond as well
 to conventional anti-inflammatory therapies and new biologics targeting asthma are less
 effective in obese asthmatics compared to lean. Very little research has been conducted in
 obese animals or obese asthmatics, resulting in a major knowledge deficit.

 A key feature of asthma is airway remodeling and fibrosis, broadly defined as a change in
 distribution, thickness, composition, mass or volume of structural components of the airway
 wall of patients relative to healthy patients. Airway remodeling is difficult to diagnose in
 obese patients as mechanical changes in chest wall compliance can contribute to the
 physiological changes seen. Classically, evidence of airway remodeling and fibrosis are
 revealed as fixed airway obstruction on spirometry. However, spirometry is not only
 insensitive to the peripheral airways, where airway remodeling occurs, but is fundamentally
 incapable of localizing the sites of remodeling and fibrosis. Thus, a critical research
 limitation in the study of airway remodeling and fibrosis in asthma is defining regions of
 disease activity to explore disease-specific mechanisms. To understand the nature of airway
 remodeling and fibrosis in obese asthma and to rapidly screen for novel therapies requires
 translation between preclinical models and patients, while using advanced imaging. Recent
 work in asthma using 3D functional imaging with 129Xe MRI has revealed the location of both
 reversible and fixed ventilation defects (defined based on bronchodilator responsivity).
 Several studies suggest that fixed defects represent sites of airway remodeling and fibrosis,
 but to date, this has been inferred indirectly from sputum analyses and CT scans. The central
 hypothesis is that sites of abnormal ventilation on 129XeMRI represent areas of airway
 remodeling and fibrosis and are enriched with fibroblasts that are invasive, proliferative
 and fibrogenic. It is further hypothesized that regional alterations in oxidant stress
 driving the production of transforming growth factor-beta (TGF-β) direct pro-remodeling
 fibroblast functions. Lastly, it is hypothesized that 129XeMRI will be a sensitive and
 specific biomarker of airway remodeling and fibrosis in obese asthmatics and rat models of
 obese asthma. By leveraging our excellence in clinical asthma, bronchoscopy, and
 translational expertise in cell function/signaling and 3D MR imaging in both patients and
 animal models, both ex vivo cell-specific mechanistic studies and in vivo animal model
 studies will be conducted to uncover the mechanisms of molecular and cellular function
 through the following Specific Aims: Aim 1) Identify the pathology, structural cell profile
 (airway fibroblast and epithelial cell) and redox status corresponding to regional areas of
 fixed and reversible post-bronchodilator defects (BD) in obese asthmatics; 2) Define the
 cellular requirement for redox-mediated TGF-β signaling between airway epithelial cells and
 fibroblasts driving regional remodeling in obese asthma; 3) Develop non-invasive 3D imaging
 techniques to assess airway regional remodeling in experimental rodent models of obese
 asthma.
Inclusion Criteria:

 Asthma Cohort INCLUSION

 -  Adequate completion of informed consent process with written documentation

 -  Male and female patients, 18 - 65 years old, inclusive

 -  Physician diagnosis of asthma for > 1 year

 -  Able to perform reproducible spirometry according to ATS criteria

 -  Post-bronchodilator FEV1 ≥ 60% of predicted at Visit 0

 -  All racial/ethnic backgrounds may participate

 -  BMI ≥ 30 kg/m2

 -  Regular treatment with ICS or ICS/LABA and/or LAMA combination medication for at least
 3 months; on a stable dose for the 4 weeks prior to Visit 0

 -  Smoking history <10 pack years and no smoking in the last 3 months

 -  Late onset asthma: Age of asthma onset (diagnosis) ≥12 years;

 -  FeNO < 25 ppb at Visit 0

 -  Negative allergen skin test

 -  Early onset asthma: Age of asthma onset (diagnosis) <12 years

 -  FeNO ≥ 25 ppb at Visit 0

 -  Positive allergen skin test

 Non-Asthma Cohort INCLUSION

 -  No history of asthma or other chronic lung diseases

 -  Male and female patients, 18 - 65 years old, inclusive

 -  Not currently smoking or using other forms of tobacco-related products (including
 vaping)

 -  Smoking history <10 pack years and no smoking in the past 3 months

 -  FEV1 > 80% of predicted and FEV1/FVC > lower limit of normal.

 -  Ability to sign consent

 -  BMI ≥ 30 kg/m2

 -  Negative allergen skin test

 Additional INCLUSION Criteria for MRI

 -  Outpatients of either gender, age > 18

 -  Willing and able to give informed consent and adhere to visit/protocol schedules.
 (Consent must be given before any study procedures are performed.)

 -  Women of childbearing potential must have a negative urine pregnancy test prior to
 MRI.

 EXCLUSION Criteria

 Asthma Cohort EXCLUSION:

 -  Respiratory tract infection within the 4 weeks prior to Visit 0

 -  Oral or systemic corticosteroid burst (for any indication) within the 4 weeks prior to
 Visit 0. One-time doses, such as intra-articular injections into a shoulder or knee
 joint, require a 4- week washout prior to Visit 0

 -  Asthma-related ER visit within the previous 4 weeks of Visit 0

 -  History of ICU admission/intubation due to asthma in the past 1 year

 -  Three or more asthma exacerbations requiring treatment with systemic corticosteroids
 in the past year consistent with severe asthma

 -  Asthma exacerbation requiring systemic corticosteroids within the 4 weeks prior to
 Visit 0

 -  Significant concomitant medical illness, including (but not limited to) heart disease,
 cancer, uncontrolled diabetes, other chronic lung diseases

 -  Chronic renal failure (creatinine > 2.0) at Visit 0

 -  Positive urine pregnancy test at Visit 0 or at any time during the study

 -  Untreated sleep apnea

 -  Participation in an intervention study (including, bronchoscopy) or use of
 investigative drugs within the past 30 days or plans to enroll in such a trial during
 the study

 -  Unable or unlikely to complete study assessments in the opinion of the Investigator

 -  Study intervention poses undue risk to patient in the opinion of the Investigator

 -  History of bronchial thermoplasty

 Non-Asthma Cohort EXCLUSION:

 -  Respiratory tract infection within the 4 weeks prior to Visit 0 Oral or systemic
 corticosteroid burst (for any indication) within the 4 weeks prior to Visit 0.
 One-time doses, such as intra-articular injections into a shoulder or knee joint,
 require a 4-week washout prior to Visit 0

 -  Significant concomitant medical illness, including (but not limited to) heart disease,
 cancer, uncontrolled diabetes, other chronic lung diseases

 -  Chronic renal failure (creatinine > 2.0) at Visit 0

 -  Positive urine pregnancy test at Visit 0 or at any time during the study

 -  Untreated sleep apnea

 -  Participation in an intervention study (including bronchoscopy) or use of
 investigative drugs within the past 30 days or plans to enroll in such a trial during
 the study

 -  Unable or unlikely to complete study assessments in the opinion of the Investigator

 -  Study intervention poses undue risk to patient in the opinion of the Investigator

 Additional EXCLUSION Criteria for MRI

 -  Medical or psychological conditions which, in the opinion of the investigator, might
 create undue risk to the subject or interfere with the subject's ability to comply
 with the protocol requirements

 -  Conditions that will prohibit MRI scanning (metal in eye, claustrophobia, inability to
 lie supine, shoulder circumference >140 cm*.) *This measurement is not an absolute as
 it can vary based on weight distribution.