Woodsmoke Particulate + Hypertonic Saline

Study Overview
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Brief Summary
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Deployment of military personnel has been associated with increased respiratory illness likely due, in part, to inhalation of unusual particulate matter (PM), such as from burn pits. Inflammation is a key initial response to inhaled particulates. The investigator has developed a protocol using inhaled wood smoke particles (WSP) as a way to study PM-induced airway inflammation. Exposure to wood smoke particles causes symptoms, even in healthy people, such as eye irritation, cough, shortness of breath, and increased mucous production. The purpose of this research study is to see if a single treatment of inhaled hypertonic saline (HS) can diminish this PM-induced airway inflammation by rapidly clearing the WSP inhaled particles from airway surfaces. The exposure will be 500 ug/m³ of WSP for 2 hours, with intermittent exercise on a bicycle and rest. The wood is burned in a typical wood stove and piped into the chamber.

Detailed Description
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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 1 (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 investigators 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 investigators 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 addition to agents with inherent anti-inflammatory and anti-oxidant properties, rapid clearance of inhaled particles from airway surfaces is a complementary approach to reduce PM-induced airway inflammation. This can be assessed through the measurement of mucociliary clearance (MCC). MCC is dependent on airway secretory cells and submucosal glands that produce a mucin-rich fluid layer on the airway surface and ciliated cells that hydrate and propel mucus out of the lung and into the upper airway. Rates of MCC are dependent on ciliary beat frequency, hydration, and the rheologic properties of mucus. In vitro studies have demonstrated that HS, through an osmotic effect on airway surfaces, improved hydration and mucus rheologic properties, and accelerated mucus transport rates. In addition, the data over the last 30 years has shown that inhaled hypertonic saline (HS) plus cough is the most effective method for acutely clearing the bronchial airways of inhaled, deposited particles. The combined effect is greater than either HS or cough alone. In the studies of asthmatics, the investigators examined the ability of a single HS treatment with a coached cough maneuver to acutely clear radiolabeled Tc99m sulfur colloid particles from airways following LPS exposure. Following HS inhalation and cough clearance maneuvers developed to recover sputum samples for analysis, the investigators observed a rapid clearance of >50% of the inhaled radiolabelled particles. The investigators hypothesize that if other pro-inflammatory particles (PMs, burn pit particles) were cleared similarly via HS-induced acceleration of MCC shortly after exposure, there would be reductions in acute PM-induced inflammation. Thus, in this study, the investigators will assess the effectiveness of inhaled 5% HS, a dose well tolerated by asthmatics at baseline and after inhaled LPS/allergen challenges for sputum induction, in mitigating WSP-induced airway neutrophilic inflammation in healthy volunteers. Normal saline 0.9% (NS) is not going to be used as a placebo treatment in this study, as inhalation of NS itself impacts the rheologic properties of mucus and MCC and thus would not be a suitable placebo. The investigators will, therefore, compare treatment with 5% HS to no receiving no treatment following WSP exposure.

Official Title
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Phase I/II Randomized Cross-over Study of Hypertonic Saline on Airway Inflammatory Response to Inhaled Wood Smoke

Conditions
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Airway Inflammation

Intervention / Treatment
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* Device: 5% Hypertonic Saline
* Other: No treatment


Participation Criteria
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Eligibility Criteria
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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. forced expiratory volume at one second (FEV1) of at least 80% of predicted and FEV1/forced vital capacity (FVC) ratio of >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). Proof of vaccination to Covid based on public health guidelines at time of inclusion 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 Positive Covid test in the past 90 days. 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: To determine the efficacy of nebulized 5% hypertonic saline (HS) (v. no treatment) in mitigating wood smoke particulate (WSP)-induced neutrophilic airway inflammation, assessed via sputum %polymorphonuclear leukocytes (PMNs), in healthy adults 4 hours post WSP exposure.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 5% Hypertonic Saline, then No Inhaled Treatment<br>Participants will receive 5% Hypertonic Saline following WSP exposure. After a 2-week washout period, participants will receive no treatment following WSP exposure. | Device: 5% Hypertonic Saline<br>* Immediately following exit from the wood smoke chamber, participants will inhale 15 mL of 5% Hypertonic Saline for 15 minutes delivered by Pari neb with a coached cough maneuver.<br>Other: No treatment<br>* No inhaled treatment will be provided immediately following exit from the wood smoke chamber.<br>|
| Active Comparator: No Inhaled Treatment, then 5% Hypertonic Saline<br>Participants will receive no inhaled treatment following WSP exposure. After a 2-week washout period, participants will receive 5% Hypertonic Saline following WSP exposure. | Device: 5% Hypertonic Saline<br>* Immediately following exit from the wood smoke chamber, participants will inhale 15 mL of 5% Hypertonic Saline for 15 minutes delivered by Pari neb with a coached cough maneuver.<br>Other: No treatment<br>* No inhaled treatment will be provided immediately following exit from the wood smoke chamber.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 4 Hours in Sputum Percent Neutrophils | Change in sputum percent neutrophils from baseline to 4 hours post WSP exposure | Baseline, 4 hours post WSP exposure | 
| Change From Baseline to 24 Hours in Sputum Percent Neutrophils | Change in sputum percent neutrophils from baseline to 24 hours post WSP exposure | Baseline, 24 hours post WSP exposure | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Number of Sputum Neutrophils | Neutrophil numbers/mg measured at 4 and 24 hours post-WSP exposure. | up to 24 hours | 
| Change in Number of Sputum Eosinophils | Eosinophil numbers/mg measured at 4 and 24 hours post-WSP exposure | up to 24 hours | 
| Change in Percent Sputum Eosinophils | Percent eosinophils measured at 4 and 24 hours post WSP exposure | up to 24 hours | 
| Change in IL-1b | IL-1b via Mesoscale platform (pg/mL) at 4 and 24 hours post WSP exposure | up to 24 hours | 
| Change in IL-6 | IL-6 via Mesoscale platform (pg/mL) at 4 and 24 hours post WSP exposure | up to 24 hours | 
| Change in IL-8 | IL-8 via Mesoscale platform (pg/mL) at 4 and 24 hours post WSP exposure | up to 24 hours | 
| Change in TNFa | TNFa via Mesoscale platform (pg/mL) at 4 and 24 hours post WSP exposure | up to 24 hours |