Genetic Screening for Inflammation Response to Wood Smoke Particles

(SmokeScreen Trial)

Overseen By Chris Brooks, BS

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: University of North Carolina, Chapel Hill

Must not be taking: Immunosuppressants, Anticoagulants, NSAIDs, others

Disqualifiers: Cardiovascular disease, Diabetes, Asthma, others

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

Compensation: Varies

Number of Visits: 3

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to study how people respond to wood smoke particles, with a focus on inflammation. Researchers are investigating whether a specific genetic trait, the GSTM1 null genotype, increases sensitivity to inflammation caused by wood smoke. The trial seeks both healthy volunteers and individuals with mild asthma who have experienced wheezing or chest tightness. Those with well-controlled asthma who do not require frequent medication might be suitable for this study. As an unphased trial, this study offers a unique opportunity to contribute to understanding how genetic traits affect inflammation response, potentially benefiting future treatments.

Do I need to stop taking my current medications for the trial?

If you have mild persistent asthma, you must stop taking Singulair, inhaled corticosteroids, or cromolyn for 2 weeks before the study visits, except for using cromolyn before exercise. Other medications may be allowed if they don't interfere with the study and have been stable for a month.

What prior data suggests that exposure to wood smoke particles is safe?

Research shows that breathing in wood smoke can irritate the lungs and cause inflammation. Some studies have found that even healthy individuals exposed to wood smoke might experience inflammation in their lungs and throughout their body. This exposure can upset the lungs and possibly weaken the immune system, increasing the likelihood of lung infections. Other research suggests that proximity to wood smoke might lead to more hospital visits for breathing issues. In some experiments, changes in genes related to inflammation have been observed, with differences noted between men and women. Additionally, studies on animals indicate that inhaling wood smoke can increase substances in the body that cause inflammation. While the safety of wood smoke remains under investigation, these findings suggest it can affect lung health. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it aims to uncover how genetic factors influence inflammation responses to wood smoke particles. Unlike existing treatments that typically focus on alleviating symptoms of inflammation using medications like corticosteroids or NSAIDs, this study explores the underlying genetic mechanisms that might predict an individual's response to environmental pollutants. By identifying specific genetic markers, the trial could pave the way for personalized approaches to managing inflammation, potentially leading to more targeted and effective prevention strategies. This could be particularly groundbreaking for those with heightened sensitivity to air pollution, offering a new angle on prevention rather than just treatment.

What evidence suggests that this trial's treatments could be effective for inflammation response to wood smoke particles?

Research shows that inhaling wood smoke particles (WSP) can irritate the airways. Studies have found that these particles can activate the body's immune system, potentially leading to airway irritation. Evidence indicates that individuals with certain genetic traits, such as the GSTM1 null genotype, might be more susceptible to this irritation. Specifically, findings suggest that people with this genetic trait could face a higher risk of airway irritation when exposed to WSP. Overall, research supports that WSP can cause significant immune and irritation responses in some individuals. Participants in this trial will be exposed to WSP to study these effects further. ^{4 6 7 8 9}

Who Is on the Research Team?

David B Peden, M.D., M.S.

Principal Investigator

Professor

Are You a Good Fit for This Trial?

This trial is for people aged 18-45 with mild asthma or allergies, who have good lung function and a low risk of cardiovascular disease. They must not smoke much, be willing to stop certain asthma medications temporarily, avoid caffeine before visits, and use reliable contraception if sexually active.

Inclusion Criteria

My lung function improved by at least 12% after treatment, or I was diagnosed with asthma after age 6.

I am allergic to specific allergens and have symptoms or a positive skin test.

I am not pregnant or have had a hysterectomy with oopherectomy.

Exclusion Criteria

I need albuterol daily for my asthma symptoms.

I experience coughing or wheezing at night more than once a week.

Positive Covid test in the past 90 days

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Woodsmoke Exposure

Participants are exposed to wood smoke particles to assess neutrophil responsiveness and the effect of the GSTM1 null genotype

1 day

1 visit (in-person)

Follow-up

Participants are monitored for changes in % neutrophils in induced sputum at 4 hours and 24 hours post-exposure

1 day

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Wood Smoke Particles (WSP)

Trial Overview Researchers are testing how wood smoke particles (WSP) affect inflammation in the lungs, particularly looking at whether a genetic factor (GSTM1 null genotype) influences this response. The study aims to identify individuals who are more or less responsive to WSP-induced inflammation.

How Is the Trial Designed?

Group I: Woodsmoke Exposure Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

University of North Carolina, Chapel Hill

Lead Sponsor

Trials

1,588

Recruited

4,364,000+

National Institute of Environmental Health Sciences (NIEHS)

Collaborator

Trials

294

Recruited

1,233,000+

Published Research Related to This Trial

Wood smoke particles (WSP) significantly increase the expression of interleukin-8 (IL-8) in primary human airway epithelial cells in a dose-dependent manner, indicating a potential inflammatory response.

The mechanism of IL-8 expression induced by WSP involves the activation of epidermal growth factor receptor (EGFR) and p38 kinase signaling pathways, suggesting targets for therapeutic intervention in airway inflammation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect and mechanism of interleukin-8 expression induced by wood smoke particles in primary human airway epithelial cells]. Yan, YJ., Wu, WD., Liu, WJ., et al.[2019]

Wood smoke particles (WSP) significantly increase reactive oxygen species in lung cells, indicating potential oxidative stress, but do not affect cell vitality or the inflammatory cytokine interleukin-8.

The toxicity of wood smoke is primarily driven by its constituents—soot, metals, and polycyclic aromatic hydrocarbons (PAHs)—with PAHs being particularly concerning due to their carcinogenic properties, suggesting that effective mitigation strategies should target all these components.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity of wood smoke particles in human A549 lung epithelial cells: the role of PAHs, soot and zinc. Dilger, M., Orasche, J., Zimmermann, R., et al.[2019]

Inhalation of hardwood smoke (HWS) by ovalbumin-sensitized mice can lead to a significant increase in eosinophils in the lungs, indicating exacerbation of allergic airway inflammation, particularly at a particulate matter concentration of 300 microg/m3.

However, HWS exposure did not significantly affect levels of key cytokines (IL-2, IL-4, IL-13, and IFN-gamma) associated with allergic responses, suggesting that while HWS can worsen some aspects of inflammation, it does not alter the overall cytokine profile in this model.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of hardwood smoke exposure on allergic airway inflammation in mice. Barrett, EG., Henson, RD., Seilkop, SK., et al.[2019]

In a study involving 10 healthy volunteers, exposure to wood smoke particles (WSP) resulted in increased systemic inflammation, as indicated by a higher percentage of neutrophils in blood tests taken 20 hours after exposure.

Despite the inflammation observed, there were no significant changes in symptoms or pulmonary function during the exposure, suggesting that even short-term exposure to WSP can trigger inflammatory responses without immediate respiratory distress.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exposure to wood smoke particles produces inflammation in healthy volunteers. Ghio, AJ., Soukup, JM., Case, M., et al.[2022]

Wood smoke particles (WSPs) from different combustion phases have similar pro-inflammatory effects, but those from medium-temperature combustion are more cytotoxic than those from high-temperature combustion, indicating that combustion conditions significantly influence toxicity.

The toxicity of WSPs is largely determined by their organic fraction, which includes compounds beyond the commonly measured polycyclic aromatic hydrocarbons (PAHs), suggesting that other organic components also play a critical role in their harmful effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Wood smoke particles from different combustion phases induce similar pro-inflammatory effects in a co-culture of monocyte and pneumocyte cell lines. Bølling, AK., Totlandsdal, AI., Sallsten, G., et al.[2022]

The study identified a specific signaling pathway in lung epithelial cells that leads to the production of interleukin-8 in response to wood smoke exposure, involving NADPH oxidase, reactive oxygen species, and AMP-activated protein kinase.

In a mouse model, blocking this pathway with Compound C reduced lung inflammation and interleukin-8 levels, suggesting that targeting this signaling mechanism could be a potential therapeutic strategy for smoke inhalation injuries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inflammatory role of AMP-activated protein kinase signaling in an experimental model of toxic smoke inhalation injury. Perng, DW., Chang, TM., Wang, JY., et al.[2017]

The study found that the 24-hour response to wood smoke particles (WSP) is more informative for assessing airway inflammation than the 6-hour response, with significant increases in inflammatory markers like IL-1beta, IL-6, and IL-8 at this later time point.

The GSTM1 null genotype and asthma status were identified as significant factors that enhance the neutrophil response to WSP exposure, indicating that genetic and health background should be considered in future studies on airways inflammation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of a screening protocol to identify persons who are responsive to wood smoke particle-induced airway inflammation with pilot assessment of GSTM1 genotype and asthma status as response modifiers. Alexis, NE., Zhou, LY., Burbank, AJ., et al.[2023]

In a study involving 20 non-smoking atopic subjects, controlled exposure to wood smoke particles did not lead to significant changes in systemic inflammation, oxidative stress, or microvascular function, indicating a lack of acute harmful effects in this population.

Despite exposure to varying concentrations of wood smoke, markers of DNA damage and inflammatory responses remained unchanged, suggesting that atopic individuals may have a different response to wood smoke compared to non-atopic individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Controlled human wood smoke exposure: oxidative stress, inflammation and microvascular function. Forchhammer, L., Møller, P., Riddervold, IS., et al.[2021]

Sub-acute exposure to wood smoke particles (WSP) in rodents improved the host response to influenza infection, leading to reduced weight loss and increased blood oxygen saturation compared to controls.

Acute WSP exposure increased airspace macrophages, while sub-acute exposure resulted in a dose-dependent increase in neutrophils, indicating that WSP exposure can modulate immune cell responses during viral infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Wood smoke particle exposure in mice reduces the severity of influenza infection. Vose, A., McCravy, M., Birukova, A., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6467301/

Wood Smoke Exposure Alters Human Inflammatory ... Furthermore, early exposure to wildfire smoke has been shown to result in sex-specific alteration of immune response to infection by attenuating systemic TLR ( ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0269749120316055

Exposure to wood smoke particles leads to inflammation ... These results suggest that wood smoke particles can enter trophoblasts and have detrimental effects early in pregnancy by disrupting critical trophoblast ...

3. particleandfibretoxicology.biomedcentral.com particleandfibretoxicology.biomedcentral.com/articles/10.1186/s12989-020-00375-x

Controlled human exposures to wood smoke: a synthesis of ... These results add to the evidence that WS exposure may induce an inflammatory response in the airways, and also suggest that individuals with ...

4. tandfonline.com tandfonline.com/doi/full/10.1080/08958378.2022.2110334

Full article: Development of a screening protocol to identify ... Development of a screening protocol to identify persons who are responsive to wood smoke particle-induced airway inflammation with pilot assessment of GSTM1 ...

5. mdpi.com mdpi.com/2571-6255/7/12/469

Effects of Wildfire Exposure on the Human Immune System This review aims to synthesize current knowledge on how wildfire smoke exposure affects the human immune system, including acute and chronic impacts.

6. epa.gov epa.gov/burnwise/wood-smoke-and-your-health

Wood Smoke and Your Health Wood smoke can irritate your lungs, cause inflammation, affect your immune system, and make you more prone to lung infections.

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/21719562/

Exposure to wood smoke particles produces inflammation ... We conclude that exposure of healthy volunteers to WSP may be associated with evidence of both systemic and pulmonary inflammation.

8. nature.com nature.com/articles/s41467-021-21708-0

Wildfire smoke impacts respiratory health more than fine ... We found increases in respiratory hospitalizations ranging from 1.3 to up to 10% with a 10 μg m −3 increase in wildfire-specific PM 2.5, compared to 0.67 to 1. ...

9. sciencedirect.com sciencedirect.com/science/article/pii/S2772829324001437

Effect of prednisone on woodsmoke-induced sputum ... Experimental data in animal models suggest that inhalation of WS can induce respiratory inflammation, as evidenced by increased cytokines or inflammatory ...