Ozone Exposure for Lung Inflammation

(MOLI Trial)

Overseen By Claudia Salazar

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Robert Tighe, MD

Must not be taking: Antihistamines, NSAIDs, Antioxidants, Vitamins

Disqualifiers: Smoking, Pregnancy, Alcohol abuse, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 5

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether previous respiratory infections, such as COVID-19, increase lung susceptibility to inflammation when exposed to environmental factors like ozone, a gas found in the air. Participants will be divided into three groups: those with no COVID history, those with a mild COVID case, and those who had COVID that affected their lungs but have since recovered. The trial seeks individuals who recall their COVID history and have been symptom-free for at least six months. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to contribute to groundbreaking insights.

Will I have to stop taking my current medications?

Participants will need to stop taking antihistamines, nonsteroidal anti-inflammatory agents, antioxidants, and certain vitamins for 1 week before and during the testing period.

Is there any evidence suggesting that ozone exposure is likely to be safe for humans?

Research shows that breathing in ozone can cause health problems. It can trigger coughing, shortness of breath, and worsen asthma or bronchitis symptoms. Evidence also suggests that long-term ozone exposure might increase the risk of death from heart and lung diseases. People often experience chest tightness and start coughing soon after exposure to high ozone levels. These findings indicate that while ozone is common in the environment, it can seriously affect lung health and overall well-being. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about using ozone for lung inflammation because it offers a novel approach to addressing respiratory conditions, especially those linked to SARS-CoV-2. Unlike traditional treatments like corticosteroids or antiviral medications, ozone therapy may work by modulating immune response and directly affecting pathogen load with its oxidative properties. This unique mechanism suggests potential for rapid symptom relief and reduced inflammation without relying on conventional drug pathways. Furthermore, ozone's ability to target different cohorts, from those with no history of SARS-CoV-2 to those with pneumonia, highlights its versatility and broad potential application.

What evidence suggests that ozone exposure could be effective for lung inflammation?

This trial will study the effects of ozone exposure on lung inflammation. Studies have shown that inhaling ozone can cause breathing problems and reduce lung function. It can lead to coughing, difficulty breathing, and worsen conditions like asthma and bronchitis. Research indicates that ozone inflames the lungs by causing oxidative stress, which damages cells. Long-term exposure to high ozone levels is linked to a quicker decline in lung function. Overall, ozone irritates the lungs and increases inflammation, especially on days with high pollution. ^{1 2 3 6 7}

Who Is on the Research Team?

Robert Tighe, MD

Principal Investigator

Duke University

Are You a Good Fit for This Trial?

This trial is for adults aged 18-55 with or without a history of mild to moderate COVID-19, who have recovered and are over 6 months post-infection with normal lung function. Excluded are those with substance abuse issues, pregnant or lactating women, individuals under the investigators' supervision, recent antibiotic use or respiratory infection, chronic cardio/pulmonary conditions, ongoing COVID-19 symptoms or abnormal lungs.

Inclusion Criteria

I had COVID-19, recovered over 6 months ago, and my lung function tests are normal.

I had COVID-19 more than 6 months ago.

I have never had COVID-19 or tested positive for it.

Exclusion Criteria

I had COVID-19 pneumonia, still have breathing issues, use oxygen, or my lung function isn't normal.

You had COVID-19 before, but you can't show a positive test result.

I can avoid taking antihistamines, NSAIDs, certain antioxidants, and vitamins for a week before and during the test.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 day

1 visit (in-person)

Initial Testing and Exposure

Participants undergo a two-day series of testing including blood draw, breathing test, and inhaled challenge with either filtered air or ozone

2 days

2 visits (in-person)

Follow-up

Participants receive follow-up phone calls 24 hours after each 2-day test series

1 day

Phone call

Second Testing and Exposure

Participants return 18-20 days later to repeat the two-day series of testing with the alternate exposure (filtered air or ozone)

2 days

2 visits (in-person)

Follow-up

Participants receive follow-up phone calls 24 hours after the second 2-day test series

1 day

Phone call

What Are the Treatments Tested in This Trial?

Interventions

• Ozone

Trial Overview The study aims to understand how previous respiratory infections like COVID-19 influence lung inflammation after being exposed to environmental factors like ozone. Participants will be divided into cohorts based on their SARS-CoV-2 infection history and assessed for lung inflammation response.

How Is the Trial Designed?

Group I: Cohort 3 Experimental Treatment 1 Intervention

SARS-CoV-2 pneumonia

Group II: Cohort 2 Experimental Treatment 1 Intervention

Documented mild SARS-CoV-2 infection

Group III: Cohort 1 Experimental Treatment 1 Intervention

No history of SARS-CoV-2

Who Is Running the Clinical Trial?

Robert Tighe, MD

Lead Sponsor

Trials

3

Recruited

140+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

National Institute of Environmental Health Sciences (NIEHS)

Collaborator

Trials

294

Recruited

1,233,000+

Published Research Related to This Trial

Short-term exposure to ozone can lead to immediate negative effects on lung function, increased airway inflammation, and higher rates of respiratory symptoms and hospital admissions.

Long-term exposure to elevated ozone levels is linked to chronic lung function decline, worsening asthma symptoms, and changes in airway cells and tissues, highlighting the need for quantitative health risk assessments using exposure-dose-response models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-effect models for ozone exposure: tool for quantitative risk estimation. van Bree, L., Marra, M., van Scheindelen, HJ., et al.[2019]

Ozone exposure leads to increased activation of the epidermal growth factor receptor (EGFR) in human bronchial epithelial cells, which is linked to airway inflammation and pulmonary function issues.

The study found that inhibiting Src kinase activity can prevent the O3-induced activation of EGFR and the subsequent increase in interleukin 8 (IL-8) expression, suggesting a potential therapeutic target for mitigating ozone-related lung inflammation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SRC-mediated EGF receptor activation regulates ozone-induced interleukin 8 expression in human bronchial epithelial cells. Wu, W., Wages, PA., Devlin, RB., et al.[2021]

Interleukin-10 (IL-10) plays a protective role against ozone (O₃)-induced pulmonary inflammation, as shown by significantly higher levels of inflammatory cells in IL-10 deficient mice compared to wild-type mice after O₃ exposure.

Gene expression analyses identified specific pathways and mediators, such as macrophage inflammatory protein 2 and cathepsin E, through which IL-10 modulates the immune response, suggesting potential therapeutic targets for protecting individuals from O₃-related lung damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protective role of interleukin-10 in ozone-induced pulmonary inflammation. Backus, GS., Howden, R., Fostel, J., et al.[2021]

A single high dose of ozone exposure in mice causes immediate damage to the respiratory epithelial barrier, leading to cell death and inflammation, but this damage is reversible if exposure is not chronic.

Chronic exposure to ozone results in irreversible lung damage, including emphysema and chronic inflammation, which is similar to the effects of other pollutants and is linked to the exacerbation of asthma and COPD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute Respiratory Barrier Disruption by Ozone Exposure in Mice. Sokolowska, M., Quesniaux, VFJ., Akdis, CA., et al.[2020]

Exposure to ambient ozone leads to airway hyperreactivity and lung inflammation, primarily through oxidative stress that activates inflammasomes and releases inflammatory cytokines like IL-1.

Understanding the mechanisms of ozone-induced lung injury may help identify new biomarkers and therapeutic targets for treating related lung diseases, such as emphysema and respiratory failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inflammasome, IL-1 and inflammation in ozone-induced lung injury. Michaudel, C., Couturier-Maillard, A., Chenuet, P., et al.[2020]

Short-term exposure to elevated ozone levels can lead to a range of respiratory effects, from mild and reversible symptoms to severe outcomes like hospital admissions.

There is a need for further research to understand the full spectrum of health effects from acute ozone exposure, including identifying sensitive groups and exploring the interaction between ozone and viral infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Examining acute health outcomes due to ozone exposure and their subsequent relationship to chronic disease outcomes. Ostro, BD.[2019]

A study involving 14 healthy, athletic subjects exposed to 0.20 ppm ozone (O3) for 4 hours showed significant increases in airway inflammation, as indicated by higher total cell counts and lactate dehydrogenase (LDH) levels in the bronchial lavage compared to filtered air exposure.

The results demonstrated that O3 exposure leads to an acute influx of inflammatory cells, particularly neutrophils, into the airways, highlighting the airway as a significant site of O3-induced injury and inflammation in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ozone-induced airway inflammation in human subjects as determined by airway lavage and biopsy. Aris, RM., Christian, D., Hearne, PQ., et al.[2013]

Ground-level ozone is a respiratory irritant that can decrease lung function and is linked to various respiratory health issues, highlighting its potential dangers to public health.

While some studies suggest that short-term increases in ozone levels may lead to higher rates of cardiopulmonary mortality, other research has found no clear connection, indicating that the effects of ozone exposure can be complex and influenced by other pollutants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outdoor air pollution: ozone health effects. Chen, TM., Gokhale, J., Shofer, S., et al.[2013]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S0160412025001424

Review article Ozone-induced lung injury and inflammation ... O3 exposure is strongly associated with respiratory issues, reduced lung function and increased risk of respiratory infections. It induces oxidative stress and ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7837374/

Health Effects of Ozone on Respiratory Diseases - PMC Recent findings suggested that long-term exposure to ozone was associated with an increased risk of cardiovascular and respiratory mortality. Longitudinal ...

3. epa.gov epa.gov/ground-level-ozone-pollution/health-effects-ozone-pollution

Health Effects of Ozone Pollution Inhaling ozone can cause coughing, shortness of breath, worse asthma or bronchitis symptoms, and irritation and damage to airways.

4. thelancet.com thelancet.com/journals/lanepe/article/PIIS2666-7762(23)00148-5/fulltext

Impact of long-term exposure to ambient ozone on lung ... The results consistently demonstrated that higher ambient ozone concentrations were associated with faster declines in spirometric lung function ...

5. hopkinsmedicine.org hopkinsmedicine.org/news/newsroom/news-releases/2019/12/exposure-to-ozone-pollution-or-wood-smoke-worsens-lung-health-of-smokers-and-former-smokers

Exposure to Ozone Pollution or Wood Smoke Worsens ... Ozone is known to irritate the lungs by increasing inflammation, and spikes of very high ozone levels — such as those that occur on hot ...

6. lung.org lung.org/research/sota/health-risks

Health Impact of Pollution | State of the Air When ozone levels are high, many people experience breathing problems such as chest tightness, coughing, and shortness of breath, often within hours of exposure ...

7. frontiersin.org frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.02518/full

Ozone Pollution: A Major Health Hazard Worldwide Ozone exposure is likely to cause premature deaths, and the evidence is stronger for mortality due to respiratory illnesses than for that due to other diseases.