Woodsmoke Particulate + Prednisone

Military deployment is associated with exposure to novel particulate matter (PM), such as
from burn pits, aeroallergens, and increased cigarette consumption. War fighters exposed to
these inhalational exposures exhibit immediate and chronic respiratory morbidity. For
example, military service personnel surveyed in both the Republic of Korea (ROK) and Kabul,
Afghanistan reported a general increase in respiratory morbidity, including asthma and
chronic bronchitis, associated with their deployment. Air contaminants in the ROK were
characterized by elevated levels of both PM 0.5-2.5 and PM 2.5-10. Similarly, exposures in
Kabul were characterized by multiple airborne PM exposures, including those from burn pits.
Burn pit PM includes metals, bioaerosols, organic by-products, and biomass combustion
particles. These findings indicate that inhaled PM is a likely cause of respiratory morbidity
in the field.

Inflammation is a key initial response to inhaled particulates. Wood smoke particles (WSP)
serve as a model agent to study PM-induced bronchitis. WSP inhalation generates reactive
oxidant (and nitrosative) species which cause local injury of airway epithelial cells and
release of damage-associated molecular patterns (DAMPs) that activate toll-like receptors
(TLR) and Interleukin (IL)-1-mediated innate immune responses by resident airway macrophages.
Contamination of PM with bioaerosols, which contain lipopolysaccharide (LPS), also activates
innate immune responses through toll-like receptor 4 (TLR4) activation of resident airway
macrophages. These complementary processes result in recruitment of neutrophils (PMN), which
mediate luminal airway inflammation with release of toxic mediators such as neutrophil
elastase and myeloperoxidase that promote acute and chronic bronchitis.

Therefore, mitigation of PM-induced airway neutrophilic inflammation should be a key focus in
order to reduce the respiratory morbidity of military personnel. The researchers have studied
a number of pro-inflammatory inhaled agents, such as nebulized LPS, ozone (O3), and WSP, as
models of acute neutrophilic bronchitis against which to test a number of therapeutic agents.
To this effect, the researchers have reported that inhaled fluticasone inhibits O3-induced
and LPS-induced neutrophilic inflammation, and that parenteral anakinra and oral
gamma-tocopherol inhibit neutrophilic responses to inhaled LPS. In this study, the
researchers will evaluate the efficacy of oral prednisone, a readily available
anti-inflammatory medication commonly used in airway inflammatory diseases, in mitigating
WSP-induced airway inflammation.

Inclusion Criteria:

- Age 18-45 years, inclusive, of both genders

- Negative pregnancy test for females who are not s/p hysterectomy with oophorectomy

- No history of episodic wheezing, chest tightness, or shortness of breath consistent
with asthma, or physician-diagnosed asthma.

- Negative methacholine challenge, by the method used in a separate screening protocol
(IRB#98-0799).

- Forced expiratory volume at one second (FEV1) of at least 80% of predicted and FEV1/
forced vital capacity (FVC) ≥0.70.

- Oxygen saturation of ≥93%

- Ability to provide an induced sputum sample.

- Subject must demonstrate a ≥10% increase in sputum %PMNs 6 hours following inhaled WSP
exposure, when compared to baseline sputum (to be completed in a separate protocol
IRB# 15-1775).

Exclusion Criteria:

Clinical contraindications:

- Any chronic medical condition considered by the PI as a contraindication to the
exposure study including significant cardiovascular disease, diabetes, chronic renal
disease, chronic thyroid disease, history of chronic infections/immunodeficiency.

- Viral upper respiratory tract infection within 4 weeks of challenge.

- Any acute infection requiring antibiotics within 4 weeks of exposure or fever of
unknown origin within 4 weeks of challenge.

- Abnormal physical findings at the baseline visit, including but not limited to
abnormalities on auscultation, temperature of 37.8° C, Systolic BP > 150mm Hg or < 85
mm Hg; or Diastolic BP > 90 mm Hg or < 50 mm Hg, or pulse oximetry saturation reading
less than 93%.

- Physician diagnosis of asthma

- If there is a history of allergic rhinitis, subjects must be asymptomatic of allergic
rhinitis at the time of study enrollment.

- 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 WSP exposure, interfere with any other
medications potentially used in the study (to include steroids, beta antagonists,
non-steroidal anti-inflammatory agents)

- Cigarette smoking > 1 pack per month

- Unwillingness to use reliable contraception if sexually active (IUD, birth control
pills/patch, condoms).

- Use of immunosuppressive or anticoagulant medications including routine use of NSAIDS.
Oral contraceptives are acceptable, as are antidepressants and other medications may
be permitted if, in the opinion of the investigator, the medication will not interfere
with the study procedures or compromise safety and if the dosage has been stable for 1
month.

- Orthopedic injuries or impediments that would preclude bicycle or treadmill exercise.

- Inability to avoid NSAIDS, Multivitamins, Vitamin C or E or herbal supplements.

- Allergy/sensitivity to study drugs or their formulations

- Pregnant/lactating women and children (< 18 years as this is age of majority in North
Carolina) will also be excluded since the risks associated with WSP exposure to the
fetus or child, respectively, are unknown and cannot be justified for this
non-therapeutic protocol. Individuals over 45 years of age will not be included due to
the increased possibility of co-morbidities and need for prohibited medications.

- Inability or unwillingness of a participant to give written informed consent