Acute and chronic inflammation are vital contributing factors to pulmonary diseases which can be triggered by the exposure to airborne toxicants such as silica and nanomaterials. There has been an increasing trend in the use of nanomaterials in various consumer products that in turn will increase the risk of pulmonary diseases. Unfortunately, there is a lack of preventative and therapeutic treatments in these diseases, in part due to a lack of understanding of key events that need to be addressed. A potential treatment that has been shown to have anti-inflammatory effects is the common dietary supplement docosahexaenoic acid (DHA); an omega-3 polyunsaturated fatty acid most commonly found in fish oil. DHA will be investigated in this proposal as both a therapeutic treatment and a prophylactic for particle-induced inflammation. Macrophages are important regulators in an immune response to inhaled foreign materials, such as silica and nanomaterials, in order to maintain homeostasis. Macrophage functions are dependent upon various signaling factors which generate different macrophage phenotypes such as pro-inflammatory classically activated M1 and anti-inflammatory alternatively activated M2 as well as the additional subsets of M2a, M2b, M2c, and M2d. Our preliminary studies and current literature suggest that DHA induces M2 macrophage phenotype polarization. Signaling factors determine which macrophage phenotype is dominant to regulate the overall response to foreign particles. I propose that exposure to various particles cause phagolysosomal membrane permeability (LMP). LMP results in cathepsin B release into the cytosol, which activates the NLRP3 inflammasome. This activation triggers active caspase-1 and leads to interleukin-1b and -18 secretion resulting in inflammation. This research will investigate the mechanisms by which DHA functions as an anti-inflammatory dietary supplement in regard to particle- induced inflammation by characterizing the impact of DHA on macrophage phenotypes and LMP. This research being performed in a nurturing environment, along with my customized training plan and the guidance of my mentor, will assist me in becoming a successful independent researcher in the future.

Public Health Relevance

Nanomaterials are known to cause pulmonary inflammation and treatment is lacking, nevertheless there has been an increase in their use within various consumer products. There has also been an increase in the consumption of fish oil which contains docosahexaenoic acid; an omega-3 fatty acid shown to decrease inflammation. This research will address the gap of knowledge in the field of inflammatory diseases in regard to understanding the mechanisms by which docosahexaenoic acid is an anti-inflammatory dietary supplement.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Humble, Michael C
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University of Montana
Schools of Pharmacy
United States
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